����JFIFXX�����    $.' ",#(7),01444'9=82<.342  2!!22222222222222222222222222222222222222222222222222����"��4�� ���,�PG"Z_�4�˷����kjز�Z�,F+��_z�,�© �����zh6�٨�ic�fu���#ډb���_�N�?��wQ���5-�~�I���8����TK<5o�Iv-�����k�_U_�����~b�M��d����Ӝ�U�Hh��?]��E�w��Q���k�{��_}qFW7HTՑ��Y��F�?_�'ϔ��_�Ջt��=||I ��6�έ"�����D���/[�k�9���Y�8ds|\���Ҿp6�Ҵ���]��.����6�z<�v��@]�i%��$j��~�g��J>��no����pM[me�i$[����s�o�ᘨ�˸ nɜG-�ĨU�ycP�3.DB�li�;��hj���x7Z^�N�h������N3u{�:j�x�힞��#M&��jL P@_���� P��&��o8������9�����@Sz6�t7#O�ߋ �s}Yf�T���lmr����Z)'N��k�۞p����w\�Tȯ?�8`�O��i{wﭹW�[�r�� ��Q4F�׊���3m&L�=��h3����z~��#�\�l :�F,j@�� ʱ�wQT����8�"kJO���6�֚l����}���R�>ډK���]��y����&����p�}b��;N�1�m�r$�|��7�>e�@B�TM*-iH��g�D�)� E�m�|�ؘbҗ�a��Ҿ����t4���o���G��*oCN�rP���Q��@z,|?W[0�����:�n,jWiE��W��$~/�hp\��?��{(�0���+�Y8rΟ�+����>S-S����VN;�}�s?.����� w�9��˟<���Mq4�Wv'��{)0�1mB��V����W[�����8�/<� �%���wT^�5���b��)iM� pg�N�&ݝ��VO~�q���u���9� ����!��J27����$O-���! �:�%H��� ـ����y�ΠM=t{!S�� oK8������t<����è:a������[�����ա�H���~��w��Qz`�po�^ ����Q��n� �,uu�C�$ ^���,������8�#��:�6��e�|~���!�3�3.�\0��q��o�4`.|� ����y�Q�`~;�d�ׯ,��O�Zw�������`73�v�܋�<���Ȏ�� ـ4k��5�K�a�u�=9Yd��$>x�A�&�� j0� ���vF��� Y�|�y��� ~�6�@c��1vOp�Ig����4��l�OD���L����� R���c���j�_�uX6��3?nk��Wy�f;^*B� ��@�~a�`��Eu������+���6�L��.ü>��}y���}_�O�6�͐�:�YrG�X��kG�����l^w���~㒶sy��Iu�!� W ��X��N�7BV��O��!X�2����wvG�R�f�T#�����t�/?���%8�^�W�aT��G�cL�M���I��(J����1~�8�?aT ���]����AS�E��(��*E}� 2��#I/�׍qz��^t�̔���b�Yz4x���t�){ OH��+(E��A&�N�������XT��o��"�XC��'���)}�J�z�p� ��~5�}�^����+�6����w��c��Q�|Lp�d�H��}�(�.|����k��c4^�"�����Z?ȕ ��a<�L�!039C� �Eu�C�F�Ew�ç ;�n?�*o���B�8�bʝ���'#Rqf���M}7����]����s2tcS{�\icTx;�\��7K���P���ʇ Z O-��~��c>"��?�������P��E��O�8��@�8��G��Q�g�a�Վ���󁶠�䧘��_%#r�>�1�z�a��eb��qcPѵ��n���#L��� =��׀t� L�7�`��V���A{�C:�g���e@�w1 Xp3�c3�ġ����p��M"'-�@n4���fG��B3�DJ�8[Jo�ߐ���gK)ƛ��$���� ���8�3�����+���� �����6�ʻ���� ���S�kI�*KZlT _`���?��K����QK�d����B`�s}�>���`��*�>��,*@J�d�oF*����弝��O}�k��s��]��y�ߘ��c1G�V���<=�7��7����6�q�PT��tXԀ�!9*4�4Tހ3XΛex�46���Y��D ����� �BdemDa����\�_l,��G�/���֌7���Y�](�xTt^%�GE�����4�}bT���ڹ�����;Y)���B�Q��u��>J/J �⮶.�XԄ��j�ݳ�+E��d ��r�5�_D�1 ��o�� �B�x�΢�#���<��W�����8���R6�@g�M�.��� dr�D��>(otU��@x=��~v���2� ӣ�d�oBd��3�eO�6�㣷�����ݜ6��6Y��Qz`��S��{���\P�~z m5{J/L��1������<�e�ͅPu�b�]�ϔ���'������f�b� Zpw��c`"��i���BD@:)ִ�:�]��hv�E�w���T�l��P���"Ju�}��وV J��G6��. J/�Qgl߭�e�����@�z�Zev2u�)]կ�����7x���s�M�-<ɯ�c��r�v�����@��$�ޮ}lk���a���'����>x��O\�ZFu>�����ck#��&:��`�$�ai�>2Δ����l���oF[h��lE�ܺ�Πk:)���`�� $[6�����9�����kOw�\|���8}������ބ:��񶐕��I�A1/�=�2[�,�!��.}gN#�u����b��� ~��݊��}34q����d�E��Lc��$��"�[q�U�硬g^��%B �z���r�pJ�ru%v\h1Y�ne`ǥ:g���pQM~�^�Xi� ��`S�:V29.�P���V�?B�k�� AEvw%�_�9C�Q����wKekPؠ�\�;Io d�{ ߞo�c1eP����\� `����E=���@K<�Y���eڼ�J���w����{av�F�'�M�@/J��+9p���|]�����Iw &`��8���&M�hg��[�{��Xj��%��Ӓ�$��(����ʹN���<>�I���RY���K2�NPlL�ɀ)��&e����B+ь����( � �JTx���_?EZ� }@ 6�U���뙢ط�z��dWI�n` D����噥�[��uV��"�G&Ú����2g�}&m��?ċ�"����Om#��������� ��{�ON��"S�X��Ne��ysQ���@Fn��Vg���dX�~nj�]J�<�K]:��FW��b�������62�=��5f����JKw��bf�X�55��~J �%^����:�-�QIE��P��v�nZum� z � ~ə ���� ���ة����;�f��\v���g�8�1��f24;�V���ǔ�)����9���1\��c��v�/'Ƞ�w�������$�4�R-��t���� e�6�/�ġ �̕Ecy�J���u�B���<�W�ַ~�w[B1L۲�-JS΂�{���΃������A��20�c#��@ 0!1@AP"#2Q`$3V�%45a6�FRUq��� ����^7ׅ,$n�������+��F�`��2X'��0vM��p�L=������5��8������u�p~���.�`r�����\���O��,ư�0oS ��_�M�����l���4�kv\JSd���x���SW�<��Ae�IX����������$I���w�:S���y���›R��9�Q[���,�5�;�@]�%���u�@ *ro�lbI �� ��+���%m:�͇ZV�����u�̉����θau<�fc�.����{�4Ա� �Q����*�Sm��8\ujqs]{kN���)qO�y�_*dJ�b�7���yQqI&9�ԌK!�M}�R�;������S�T���1���i[U�ɵz�]��U)V�S6���3$K{�ߊ<�(� E]Զ[ǼENg�����'�\?#)Dkf��J���o��v���'�%ƞ�&K�u�!��b�35LX�Ϸ��63$K�a�;�9>,R��W��3�3� d�JeTYE.Mϧ��-�o�j3+y��y^�c�������VO�9NV\nd�1 ��!͕_)a�v;����թ�M�lWR1��)El��P;��yوÏ�u 3�k�5Pr6<�⒲l�!˞*��u־�n�!�l:����UNW ��%��Chx8vL'��X�@��*��)���̮��ˍ��� ���D-M�+J�U�kvK����+�x8��cY������?�Ԡ��~3mo��|�u@[XeY�C�\Kp�x8�oC�C�&����N�~3-H���� ��MX�s�u<`���~"WL��$8ξ��3���a�)|:@�m�\���^�`�@ҷ)�5p+��6���p�%i)P M���ngc�����#0Aruz���RL+xSS?���ʮ}()#�t��mˇ!��0}}y����<�e� �-ή�Ԩ��X������ MF���ԙ~l L.3���}�V뽺�v�����멬��Nl�)�2����^�Iq��a��M��qG��T�����c3#������3U�Ǎ���}��לS�|qa��ڃ�+���-��2�f����/��bz��ڐ�� �ݼ[2�ç����k�X�2�* �Z�d���J�G����M*9W���s{��w���T��x��y,�in�O�v��]���n����P�$�JB@=4�OTI�n��e�22a\����q�d���%�$��(���:���: /*�K[PR�fr\nڙdN���F�n�$�4�[�� U�zƶ����� �mʋ���,�ao�u 3�z� �x��Kn����\[��VFmbE;�_U��&V�Gg�]L�۪&#n%�$ɯ�dG���D�TI=�%+AB�Ru#��b4�1�»x�cs�YzڙJG��f��Il��d�eF'T� iA��T���uC�$����Y��H?����[!G`}���ͪ� �纤Hv\������j�Ex�K���!���OiƸ�Yj�+u-<���'q����uN�*�r\��+�]���<�wOZ.fp�ێ��,-*)V?j-kÊ#�`�r��dV����(�ݽBk�����G�ƛk�QmUڗe��Z���f}|����8�8��a���i��3'J�����~G_�^���d�8w������ R�`(�~�.��u���l�s+g�bv���W���lGc}��u���afE~1�Ue������Z�0�8�=e�� f@/�jqEKQQ�J��oN��J���W5~M>$6�Lt�;$ʳ{���^��6�{����v6���ķܰg�V�cnn �~z�x�«�,2�u�?cE+Ș�H؎�%�Za�)���X>uW�Tz�Nyo����s���FQƤ��$��*�&�LLXL)�1�" L��eO��ɟ�9=���:t��Z���c��Ž���Y?�ӭV�wv�~,Y��r�ۗ�|�y��GaF�����C�����.�+� ���v1���fήJ�����]�S��T��B��n5sW}y�$��~z�'�c ��8 ��� ,! �p��VN�S��N�N�q��y8z˱�A��4��*��'������2n<�s���^ǧ˭P�Jޮɏ�U�G�L�J�*#��<�V��t7�8����TĜ>��i}K%,���)[��z�21z ?�N�i�n1?T�I�R#��m-�����������������1����lA�`��fT5+��ܐ�c�q՝��ʐ��,���3�f2U�եmab��#ŠdQ�y>\��)�SLY����w#��.���ʑ�f��� ,"+�w�~�N�'�c�O�3F�������N<���)j��&��,-� �љ���֊�_�zS���TǦ����w�>��?�������n��U仆�V���e�����0���$�C�d���rP �m�׈e�Xm�Vu� �L��.�bֹ��� �[Դaզ���*��\y�8�Է:�Ez\�0�Kq�C b��̘��cө���Q��=0Y��s�N��S.���3.���O�o:���#���v7�[#߫ ��5�܎�L���Er4���9n��COWlG�^��0k�%<���ZB���aB_���������'=��{i�v�l�$�uC���mƎҝ{�c㱼�y]���W�i ��ߧc��m�H� m�"�"�����;Y�ߝ�Z�Ǔ�����:S#��|}�y�,/k�Ld� TA�(�AI$+I3��;Y*���Z��}|��ӧO��d�v��..#:n��f>�>���ȶI�TX��� 8��y����"d�R�|�)0���=���n4��6ⲑ�+��r<�O�܂~zh�z����7ܓ�HH�Ga롏���nCo�>������a ���~]���R���̲c?�6(�q�;5%� |�uj�~z8R=X��I�V=�|{v�Gj\gc��q����z�؋%M�ߍ����1y��#��@f^���^�>N�����#x#۹��6�Y~�?�dfPO��{��P�4��V��u1E1J �*|���%���JN��`eWu�zk M6���q t[�� ��g�G���v��WIG��u_ft����5�j�"�Y�:T��ɐ���*�;� e5���4����q$C��2d�}���� _S�L#m�Yp��O�.�C�;��c����Hi#֩%+) �Ӎ��ƲV���SYź��g |���tj��3�8���r|���V��1#;.SQ�A[���S������#���`n�+���$��$I �P\[�@�s��(�ED�z���P��])8�G#��0B��[ى��X�II�q<��9�~[Z멜�Z�⊔IWU&A>�P~�#��dp<�?����7���c��'~���5 ��+$���lx@�M�dm��n<=e�dyX��?{�|Aef ,|n3�<~z�ƃ�uۧ�����P��Y,�ӥQ�*g�#먙R�\���;T��i,��[9Qi歉����c>]9�� ��"�c��P�� �Md?٥��If�ت�u��k��/����F��9�c*9��Ǎ:�ØF���z�n*�@|I�ށ9����N3{'��[�'ͬ�Ҳ4��#}��!�V� Fu��,�,mTIk���v C�7v���B�6k�T9��1�*l� '~��ƞF��lU��'�M ����][ΩũJ_�{�i�I�n��$���L�� j��O�dx�����kza۪��#�E��Cl����x˘�o�����V���ɞ�ljr��)�/,�߬h�L��#��^��L�ф�,íMƁe�̩�NB�L�����iL����q�}��(��q��6IçJ$�W�E$��:������=#����(�K�B����zђ <��K(�N�۫K�w��^O{!����)�H���>x�������lx�?>Պ�+�>�W���,Ly!_�D���Ō�l���Q�!�[ �S����J��1��Ɛ�Y}��b,+�Lo�x�ɓ)����=�y�oh�@�꥟/��I��ѭ=��P�y9��� �ۍYӘ�e+�p�Jnϱ?V\SO%�(�t� ���=?MR�[Ș�����d�/ ��n�l��B�7j� ��!�;ӥ�/�[-���A�>�dN�sLj ��,ɪv��=1c�.SQ�O3�U���ƀ�ܽ�E����������̻��9G�ϷD�7(�}��Ävӌ\�y�_0[w ���<΍>����a_��[0+�L��F.�޺��f�>oN�T����q;���y\��bՃ��y�jH�<|q-eɏ�_?_9+P���Hp$�����[ux�K w�Mw��N�ی'$Y2�=��q���KB��P��~������Yul:�[<����F1�2�O���5=d����]Y�sw:���Ϯ���E��j,_Q��X��z`H1,#II ��d�wr��P˂@�ZJV����y$�\y�{}��^~���[:N����ߌ�U�������O��d�����ؾe��${p>G��3c���Ė�lʌ�� ת��[��`ϱ�-W����dg�I��ig2��� ��}s ��ؤ(%#sS@���~���3�X�nRG�~\jc3�v��ӍL��M[JB�T��s3}��j�Nʖ��W����;7��ç?=X�F=-�=����q�ߚ���#���='�c��7���ڑW�I(O+=:uxq�������������e2�zi+�kuG�R��������0�&e�n���iT^J����~\jy���p'dtG��s����O��3����9* �b#Ɋ�� p������[Bws�T�>d4�ۧs���nv�n���U���_�~,�v����ƜJ1��s�� �QIz��)�(lv8M���U=�;����56��G���s#�K���MP�=��LvyGd��}�VwWBF�'�à �?MH�U�g2�� ����!�p�7Q��j��ڴ����=��j�u��� Jn�A s���uM������e��Ɔ�Ҕ�!)'��8Ϣ�ٔ��ޝ(��Vp���צ֖d=�IC�J�Ǡ{q������kԭ�߸���i��@K����u�|�p=..�*+����x�����z[Aqġ#s2a�Ɗ���RR�)*HRsi�~�a &f��M��P����-K�L@��Z��Xy�'x�{}��Zm+���:�)�) IJ�-i�u���� ���ܒH��'�L(7�y�GӜq���� j��� 6ߌg1�g�o���,kر���tY�?W,���p���e���f�OQS��!K�۟cҒA�|ս�j�>��=⬒��˧L[�� �߿2JaB~R��u�:��Q�] �0H~���]�7��Ƽ�I���(}��cq '�ήET���q�?f�ab���ӥvr� �)o��-Q��_'����ᴎo��K������;��V���o��%���~OK ����*��b�f:���-ťIR��`B�5!RB@���ï�� �u �̯e\�_U�_������� g�ES��3�������QT��a����x����U<~�c?�*�#]�MW,[8O�a�x��]�1bC|踤�P��lw5V%�)�{t�<��d��5���0i�XSU��m:��Z�┵�i�"��1�^B�-��P�hJ��&)O��*�D��c�W��vM��)����}���P��ܗ-q����\mmζZ-l@�}��a��E�6��F�@��&Sg@���ݚ�M����� ȹ 4����#p�\H����dYDo�H���"��\��..R�B�H�z_�/5˘����6��KhJR��P�mƶi�m���3�,#c�co��q�a)*Pt����R�m�k�7x�D�E�\Y�閣_X�<���~�)���c[[�BP����6�Yq���S��0����%_����;��Àv�~�| VS؇ ��'O0��F0��\���U�-�d@�����7�SJ*z��3n��y��P����O���������m�~�P�3|Y��ʉr#�C�<�G~�.,! ���bqx���h~0=��!ǫ�jy����l�O,�[B��~��|9��ٱ����Xly�#�i�B��g%�S��������tˋ���e���ې��\[d�t)��.+u�|1 ������#�~Oj����hS�%��i.�~X���I�H�m��0n���c�1uE�q��cF�RF�o���7� �O�ꮧ� ���ۛ{��ʛi5�rw?׌#Qn�TW��~?y$��m\�\o����%W� ?=>S�N@�� �Ʈ���R����N�)�r"C�:��:����� �����#��qb��Y�. �6[��2K����2u�Ǧ�HYR��Q�MV��� �G�$��Q+.>�����nNH��q�^��� ����q��mM��V��D�+�-�#*�U�̒ ���p욳��u:�������IB���m���PV@O���r[b= �� ��1U�E��_Nm�yKbN�O���U�}�the�`�|6֮P>�\2�P�V���I�D�i�P�O;�9�r�mAHG�W�S]��J*�_�G��+kP�2����Ka�Z���H�'K�x�W�MZ%�O�YD�Rc+o��?�q��Ghm��d�S�oh�\�D�|:W������UA�Qc yT�q������~^�H��/��#p�CZ���T�I�1�ӏT����4��"�ČZ�����}��`w�#�*,ʹ�� ��0�i��課�Om�*�da��^gJ݅{���l�e9uF#T�ֲ��̲�ٞC"�q���ߍ ոޑ�o#�XZTp����@ o�8��(jd��xw�]�,f���`~�|,s��^����f�1���t��|��m�򸄭/ctr��5s��7�9Q�4�H1꠲BB@l9@���C�����+�wp�xu�£Yc�9��?`@#�o�mH�s2��)�=��2�.�l����jg�9$�Y�S�%*L������R�Y������7Z���,*=�䷘$�������arm�o�ϰ���UW.|�r�uf����IGw�t����Zwo��~5 ��YյhO+=8fF�)�W�7�L9lM�̘·Y���֘YLf�큹�pRF���99.A �"wz��=E\Z���'a� 2��Ǚ�#;�'}�G���*��l��^"q��+2FQ� hj��kŦ��${���ޮ-�T�٭cf�|�3#~�RJ����t��$b�(R��(����r���dx� >U b�&9,>���%E\� Ά�e�$��'�q't��*�א���ެ�b��-|d���SB�O�O��$�R+�H�)�܎�K��1m`;�J�2�Y~9��O�g8=vqD`K[�F)k�[���1m޼c��n���]s�k�z$@��)!I �x՝"v��9=�ZA=`Ɠi �:�E��)`7��vI��}d�YI�_ �o�:ob���o ���3Q��&D&�2=�� �Ά��;>�h����y.*ⅥS������Ӭ�+q&����j|UƧ����}���J0��WW< ۋS�)jQR�j���Ư��rN)�Gű�4Ѷ(�S)Ǣ�8��i��W52���No˓� ۍ%�5brOn�L�;�n��\G����=�^U�dI���8$�&���h��'���+�(������cȁ߫k�l��S^���cƗjԌE�ꭔ��gF���Ȓ��@���}O���*;e�v�WV���YJ\�]X'5��ղ�k�F��b 6R�o՜m��i N�i����>J����?��lPm�U��}>_Z&�KK��q�r��I�D�Չ~�q�3fL�:S�e>���E���-G���{L�6p�e,8��������QI��h��a�Xa��U�A'���ʂ���s�+טIjP�-��y�8ۈZ?J$��W�P� ��R�s�]��|�l(�ԓ��sƊi��o(��S0��Y� 8�T97.�����WiL��c�~�dxc�E|�2!�X�K�Ƙਫ਼�$((�6�~|d9u+�qd�^3�89��Y�6L�.I�����?���iI�q���9�)O/뚅����O���X��X�V��ZF[�یgQ�L��K1���RҖr@v�#��X�l��F���Нy�S�8�7�kF!A��sM���^rkp�jP�DyS$N���q��nxҍ!U�f�!eh�i�2�m���`�Y�I�9r�6� �TF���C}/�y�^���Η���5d�'��9A-��J��>{�_l+�`��A���[�'��յ�ϛ#w:݅�%��X�}�&�PSt�Q�"�-��\縵�/����$Ɨh�Xb�*�y��BS����;W�ջ_mc�����vt?2}1�;qS�d�d~u:2k5�2�R�~�z+|HE!)�Ǟl��7`��0�<�,�2*���Hl-��x�^����'_TV�gZA�'j� ^�2Ϊ��N7t�����?w�� �x1��f��Iz�C-Ȗ��K�^q�;���-W�DvT�7��8�Z�������� hK�(P:��Q- �8�n�Z���܃e貾�<�1�YT<�,�����"�6{/ �?�͟��|1�:�#g��W�>$����d��J��d�B��=��jf[��%rE^��il:��B���x���Sּ�1հ��,�=��*�7 fcG��#q� �eh?��2�7�����,�!7x��6�n�LC�4x��},Geǝ�tC.��vS �F�43��zz\��;QYC,6����~;RYS/6���|2���5���v��T��i����������mlv��������&� �nRh^ejR�LG�f���? �ۉҬܦƩ��|��Ȱ����>3����!v��i�ʯ�>�v��オ�X3e���_1z�Kȗ\<������!�8���V��]��?b�k41�Re��T�q��mz��TiOʦ�Z��Xq���L������q"+���2ۨ��8}�&N7XU7Ap�d�X��~�׿��&4e�o�F��� �H����O���č�c�� 懴�6���͉��+)��v;j��ݷ�� �UV�� i��� j���Y9GdÒJ1��詞�����V?h��l����l�cGs�ځ�������y�Ac�����\V3�? �� ܙg�>qH�S,�E�W�[�㺨�uch�⍸�O�}���a��>�q�6�n6����N6�q������N ! 1AQaq�0@����"2BRb�#Pr���3C`��Scst���$4D���%Td�� ?���N����a��3��m���C���w��������xA�m�q�m���m������$����4n淿t'��C"w��zU=D�\R+w�p+Y�T�&�պ@��ƃ��3ޯ?�Aﶂ��aŘ���@-�����Q�=���9D��ռ�ѻ@��M�V��P��܅�G5�f�Y<�u=,EC)�<�Fy'�"�&�չ�X~f��l�KԆV��?�� �W�N����=(� �;���{�r����ٌ�Y���h{�١������jW����P���Tc�����X�K�r��}���w�R��%��?���E��m�� �Y�q|����\lEE4���r���}�lsI�Y������f�$�=�d�yO����p�����yBj8jU�o�/�S��?�U��*������ˍ�0������u�q�m [�?f����a�� )Q�>����6#������� ?����0UQ����,IX���(6ڵ[�DI�MNލ�c&���υ�j\��X�R|,4��� j������T�hA�e��^���d���b<����n�� �즇�=!���3�^�`j�h�ȓr��jẕ�c�,ٞX����-����a�ﶔ���#�$��]w�O��Ӫ�1y%��L�Y<�wg#�ǝ�̗`�x�xa�t�w��»1���o7o5��>�m뭛C���Uƃߜ}�C���y1Xνm�F8�jI���]����H���ۺиE@I�i;r�8ӭ����V�F�Շ| ��&?�3|x�B�MuS�Ge�=Ӕ�#BE5G�����Y!z��_e��q�р/W>|-�Ci߇�t�1ޯќd�R3�u��g�=0 5��[?�#͏��q�cf���H��{ ?u�=?�?ǯ���}Z��z���hmΔ�BFTW�����<�q�(v� ��!��z���iW]*�J�V�z��gX֧A�q�&��/w���u�gYӘa���; �i=����g:��?2�dž6�ى�k�4�>�Pxs����}������G�9��3 ���)gG�R<>r h�$��'nc�h�P��Bj��J�ҧH� -��N1���N��?��~��}-q!=��_2hc�M��l�vY%UE�@|�v����M2�.Y[|y�"Eï��K�ZF,�ɯ?,q�?v�M 80jx�"�;�9vk�����+ ֧�� �ȺU��?�%�vcV��mA�6��Qg^M����A}�3�nl� QRN�l8�kkn�'�����(��M�7m9و�q���%ޟ���*h$Zk"��$�9��: �?U8�Sl��,,|ɒ��xH(ѷ����Gn�/Q�4�P��G�%��Ա8�N��!� �&�7�;���eKM7�4��9R/%����l�c>�x;������>��C�:�����t��h?aKX�bhe�ᜋ^�$�Iհ �hr7%F$�E��Fd���t��5���+�(M6�t����Ü�UU|zW�=a�Ts�Tg������dqP�Q����b'�m���1{|Y����X�N��b �P~��F^F:����k6�"�j!�� �I�r�`��1&�-$�Bevk:y���#yw��I0��x��=D�4��tU���P�ZH��ڠ底taP��6����b>�xa����Q�#� WeF��ŮNj�p�J* mQ�N����*I�-*�ȩ�F�g�3 �5��V�ʊ�ɮ�a��5F���O@{���NX��?����H�]3��1�Ri_u��������ѕ�� ����0��� F��~��:60�p�͈�S��qX#a�5>���`�o&+�<2�D����: �������ڝ�$�nP���*)�N�|y�Ej�F�5ټ�e���ihy�Z �>���k�bH�a�v��h�-#���!�Po=@k̆IEN��@��}Ll?j�O������߭�ʞ���Q|A07x���wt!xf���I2?Z��<ץ�T���cU�j��]��陎Ltl �}5�ϓ��$�,��O�mˊ�;�@O��jE��j(�ا,��LX���LO���Ц�90�O �.����a��nA���7������j4 ��W��_ٓ���zW�jcB������y՗+EM�)d���N�g6�y1_x��p�$Lv:��9�"z��p���ʙ$��^��JԼ*�ϭ����o���=x�Lj�6�J��u82�A�H�3$�ٕ@�=Vv�]�'�qEz�;I˼��)��=��ɯ���x �/�W(V���p�����$ �m�������u�����񶤑Oqˎ�T����r��㠚x�sr�GC��byp�G��1ߠ�w e�8�$⿄����/�M{*}��W�]˷.�CK\�ުx���/$�WPw���r� |i���&�}�{�X� �>��$-��l���?-z���g����lΆ���(F���h�vS*���b���߲ڡn,|)mrH[���a�3�ר�[1��3o_�U�3�TC�$��(�=�)0�kgP���� ��u�^=��4 �WYCҸ:��vQ�ר�X�à��tk�m,�t*��^�,�}D*� �"(�I��9R����>`�`��[~Q]�#af��i6l��8���6�:,s�s�N6�j"�A4���IuQ��6E,�GnH��zS�HO�uk�5$�I�4��ؤ�Q9�@��C����wp�BGv[]�u�Ov���0I4���\��y�����Q�Ѹ��~>Z��8�T��a��q�ޣ;z��a���/��S��I:�ܫ_�|������>=Z����8:�S��U�I�J��"IY���8%b8���H��:�QO�6�;7�I�S��J��ҌAά3��>c���E+&jf$eC+�z�;��V����� �r���ʺ������my�e���aQ�f&��6�ND��.:��NT�vm�<- u���ǝ\MvZY�N�NT��-A�>jr!S��n�O 1�3�Ns�%�3D@���`������ܟ 1�^c<���� �a�ɽ�̲�Xë#�w�|y�cW�=�9I*H8�p�^(4���՗�k��arOcW�tO�\�ƍR��8����'�K���I�Q�����?5�>[�}��yU�ײ -h��=��% q�ThG�2�)���"ו3]�!kB��*p�FDl�A���,�eEi�H�f�Ps�����5�H:�Փ~�H�0Dت�D�I����h�F3�������c��2���E��9�H��5�zԑ�ʚ�i�X�=:m�xg�hd(�v����׊�9iS��O��d@0ڽ���:�p�5�h-��t�&���X�q�ӕ,��ie�|���7A�2���O%P��E��htj��Y1��w�Ѓ!����  ���� ࢽ��My�7�\�a�@�ţ�J �4�Ȼ�F�@o�̒?4�wx��)��]�P��~�����u�����5�����7X ��9��^ܩ�U;Iꭆ 5 �������eK2�7(�{|��Y׎ �V��\"���Z�1� Z�����}��(�Ǝ"�1S���_�vE30>���p;� ΝD��%x�W�?W?v����o�^V�i�d��r[��/&>�~`�9Wh��y�;���R��� ;;ɮT��?����r$�g1�K����A��C��c��K��l:�'��3 c�ﳯ*"t8�~l��)���m��+U,z��`(�>yJ�?����h>��]��v��ЍG*�{`��;y]��I�T� ;c��NU�fo¾h���/$���|NS���1�S�"�H��V���T���4��uhǜ�]�v;���5�͠x��'C\�SBpl���h}�N����� A�Bx���%��ޭ�l��/����T��w�ʽ]D�=����K���ž�r㻠l4�S�O?=�k �M:� ��c�C�a�#ha���)�ѐxc�s���gP�iG��{+���x���Q���I= �� z��ԫ+ �8"�k�ñ�j=|����c ��y��CF��/��*9ж�h{ �?4�o� ��k�m�Q�N�x��;�Y��4膚�a�w?�6�>e]�����Q�r�:����g�,i"�����ԩA�*M�<�G��b�if��l^M��5� �Ҩ�{����6J��ZJ�����P�*�����Y���ݛu�_4�9�I8�7���������,^ToR���m4�H��?�N�S�ѕw��/S��甍�@�9H�S�T��t�ƻ���ʒU��*{Xs�@����f�����֒Li�K{H�w^���������Ϥm�tq���s� ���ք��f:��o~s��g�r��ט� �S�ѱC�e]�x���a��) ���(b-$(�j>�7q�B?ӕ�F��hV25r[7 Y� }L�R��}����*sg+��x�r�2�U=�*'WS��ZDW]�WǞ�<��叓���{�$�9Ou4��y�90-�1�'*D`�c�^o?(�9��u���ݐ��'PI&� f�Jݮ�������:wS����jfP1F:X �H�9dԯ���˝[�_54 �}*;@�ܨ�� ð�yn�T���?�ןd�#���4rG�ͨ��H�1�|-#���Mr�S3��G�3�����)�.᧏3v�z֑��r����$G"�`j �1t��x0<Ɔ�Wh6�y�6��,œ�Ga��gA����y��b��)��h�D��ß�_�m��ü �gG;��e�v��ݝ�nQ� ��C����-�*��o���y�a��M��I�>�<���]obD��"�:���G�A��-\%LT�8���c�)��+y76���o�Q�#*{�(F�⽕�y����=���rW�\p���۩�c���A���^e6��K������ʐ�cVf5$�'->���ՉN"���F�"�UQ@�f��Gb~��#�&�M=��8�ט�JNu9��D��[̤�s�o�~������ G��9T�tW^g5y$b��Y'��س�Ǵ�=��U-2 #�MC�t(�i� �lj�@Q 5�̣i�*�O����s�x�K�f��}\��M{E�V�{�υ��Ƈ�����);�H����I��fe�Lȣr�2��>��W�I�Ȃ6������i��k�� �5�YOxȺ����>��Y�f5'��|��H+��98pj�n�.O�y�������jY��~��i�w'������l�;�s�2��Y��:'lg�ꥴ)o#'Sa�a�K��Z� �m��}�`169�n���"���x��I ��*+� }F<��cГ���F�P�������ֹ*�PqX�x۩��,� ��N�� �4<-����%����:��7����W���u�`����� $�?�I��&����o��o��`v�>��P��"��l���4��5'�Z�gE���8���?��[�X�7(��.Q�-��*���ތL@̲����v��.5���[��=�t\+�CNܛ��,g�SQnH����}*F�G16���&:�t��4ُ"A��̣��$�b �|����#rs��a�����T�� ]�<�j��BS�('$�ɻ� �wP;�/�n��?�ݜ��x�F��yUn�~mL*-�������Xf�wd^�a�}��f�,=t�׵i�.2/wpN�Ep8�OР���•��R�FJ� 55TZ��T �ɭ�<��]��/�0�r�@�f��V��V����Nz�G��^���7hZi����k��3�,kN�e|�vg�1{9]_i��X5y7� 8e]�U����'�-2,���e"����]ot�I��Y_��n�(JҼ��1�O ]bXc���Nu�No��pS���Q_���_�?i�~�x h5d'�(qw52] ��'ޤ�q��o1�R!���`ywy�A4u���h<קy���\[~�4�\ X�Wt/� 6�����n�F�a8��f���z �3$�t(���q��q�x��^�XWeN'p<-v�!�{�(>ӽDP7��ո0�y)�e$ٕv�Ih'Q�EA�m*�H��RI��=:��� ���4牢) �%_iN�ݧ�l]� �Nt���G��H�L��� ɱ�g<���1V�,�J~�ٹ�"K��Q�� 9�HS�9�?@��k����r�;we݁�]I�!{ �@�G�[�"��`���J:�n]�{�cA�E����V��ʆ���#��U9�6����j�#Y�m\��q�e4h�B�7��C�������d<�?J����1g:ٳ���=Y���D�p�ц� ׈ǔ��1�]26؜oS�'��9�V�FVu�P�h�9�xc�oq�X��p�o�5��Ա5$�9W�V(�[Ak�aY錎qf;�'�[�|���b�6�Ck��)��#a#a˙��8���=äh�4��2��C��4tm^ �n'c���]GQ$[Wҿ��i���vN�{Fu ��1�gx��1┷���N�m��{j-,��x�� Ūm�ЧS�[�s���Gna���䑴�� x�p 8<������97�Q���ϴ�v�aϚG��Rt�Һ׈�f^\r��WH�JU�7Z���y)�vg=����n��4�_)y��D'y�6�]�c�5̪�\� �PF�k����&�c;��cq�$~T�7j ���nç]�<�g ":�to�t}�159�<�/�8������m�b�K#g'I'.W�����6��I/��>v��\�MN��g���m�A�yQL�4u�Lj�j9��#44�t��l^�}L����n��R��!��t��±]��r��h6ٍ>�yҏ�N��fU�� ���� Fm@�8}�/u��jb9������he:A�y�ծw��GpΧh�5����l}�3p468��)U��d��c����;Us/�֔�YX�1�O2��uq�s��`hwg�r~�{ R��mhN��؎*q 42�*th��>�#���E����#��Hv�O����q�}�����6�e��\�,Wk�#���X��b>��p}�դ��3���T5��†��6��[��@�P�y*n��|'f�֧>�lư΂�̺����SU�'*�q�p�_S�����M�� '��c�6�����m�� ySʨ;M��r���Ƌ�m�Kxo,���Gm�P��A�G�:��i��w�9�}M(�^�V��$ǒ�ѽ�9���|���� �a����J�SQ�a���r�B;����}���ٻ֢�2�%U���c�#�g���N�a�ݕ�'�v�[�OY'��3L�3�;,p�]@�S��{ls��X�'���c�jw�k'a�.��}�}&�� �dP�*�bK=ɍ!����;3n�gΊU�ߴmt�'*{,=SzfD� A��ko~�G�aoq�_mi}#�m�������P�Xhύ����mxǍ�΂���巿zf��Q���c���|kc�����?���W��Y�$���_Lv����l߶��c���`?����l�j�ݲˏ!V��6����U�Ђ(A���4y)H���p�Z_�x��>���e��R��$�/�`^'3qˏ�-&Q�=?��CFVR �D�fV�9��{�8g�������n�h�(P"��6�[�D���< E�����~0<@�`�G�6����Hг�cc�� �c�K.5��D��d�B���`?�XQ��2��ٿyqo&+�1^� DW�0�ꊩ���G�#��Q�nL3��c���������/��x ��1�1[y�x�პCW��C�c�UĨ80�m�e�4.{�m��u���I=��f�����0QRls9���f���������9���~f�����Ǩ��a�"@�8���ȁ�Q����#c�ic������G��$���G���r/$W�(��W���V�"��m�7�[m�A�m����bo��D� j����۳� l���^�k�h׽����� ��#� iXn�v��eT�k�a�^Y�4�BN��ĕ��0 !01@Q"2AaPq3BR������?���@4�Q�����T3,���㺠�W�[=JK�Ϟ���2�r^7��vc�:�9 �E�ߴ�w�S#d���Ix��u��:��Hp��9E!�� V 2;73|F��9Y���*ʬ�F��D����u&���y؟��^EA��A��(ɩ���^��GV:ݜDy�`��Jr29ܾ�㝉��[���E;Fzx��YG��U�e�Y�C���� ����v-tx����I�sם�Ę�q��Eb�+P\ :>�i�C'�;�����k|z�رn�y]�#ǿb��Q��������w�����(�r|ӹs��[�D��2v-%��@;�8<a���[\o[ϧw��I!��*0�krs)�[�J9^��ʜ��p1)� "��/_>��o��<1����A�E�y^�C��`�x1'ܣn�p��s`l���fQ��):�l����b>�Me�jH^?�kl3(�z:���1ŠK&?Q�~�{�ٺ�h�y���/�[��V�|6��}�KbX����mn[-��7�5q�94�������dm���c^���h� X��5��<�eޘ>G���-�}�دB�ޟ� ��|�rt�M��V+�]�c?�-#ڛ��^ǂ}���Lkr���O��u�>�-D�ry� D?:ޞ�U��ǜ�7�V��?瓮�"�#���r��չģVR;�n���/_� ؉v�ݶe5d�b9��/O��009�G���5n�W����JpA�*�r9�>�1��.[t���s�F���nQ� V 77R�]�ɫ8����_0<՜�IF�u(v��4��F�k�3��E)��N:��yڮe��P�`�1}�$WS��J�SQ�N�j�ٺ��޵�#l���ј(�5=��5�lǏmoW�v-�1����v,W�mn��߀$x�<����v�j(����c]��@#��1������Ǔ���o'��u+����;G�#�޸��v-lη��/(`i⣍Pm^���ԯ̾9Z��F��������n��1��� ��]�[��)�'������:�֪�W��FC����� �B9،!?���]��V��A�Վ�M��b�w��G F>_DȬ0¤�#�QR�[V��kz���m�w�"��9ZG�7'[��=�Q����j8R?�zf�\a�=��O�U����*oB�A�|G���2�54 �p��.w7� �� ��&������ξxGHp� B%��$g�����t�Џ򤵍z���HN�u�Я�-�'4��0��;_��3 !01"@AQa2Pq#3BR������?��ʩca��en��^��8���<�u#��m*08r��y�N"�<�Ѳ0��@\�p��� �����Kv�D��J8�Fҽ� �f�Y��-m�ybX�NP����}�!*8t(�OqѢ��Q�wW�K��ZD��Δ^e��!� ��B�K��p~�����e*l}z#9ң�k���q#�Ft�o��S�R����-�w�!�S���Ӥß|M�l޶V��!eˈ�8Y���c�ЮM2��tk���� ������J�fS����Ö*i/2�����n]�k�\���|4yX�8��U�P.���Ы[���l��@"�t�<������5�lF���vU�����W��W��;�b�cД^6[#7@vU�xgZv��F�6��Q,K�v��� �+Ъ��n��Ǣ��Ft���8��0��c�@�!�Zq s�v�t�;#](B��-�nῃ~���3g������5�J�%���O������n�kB�ĺ�.r��+���#�N$?�q�/�s�6��p��a����a��J/��M�8��6�ܰ"�*������ɗud"\w���aT(����[��F��U՛����RT�b���n�*��6���O��SJ�.�ij<�v�MT��R\c��5l�sZB>F��<7�;EA��{��E���Ö��1U/�#��d1�a�n.1ě����0�ʾR�h��|�R��Ao�3�m3 ��%�� ���28Q� ��y��φ���H�To�7�lW>����#i`�q���c����a��� �m,B�-j����݋�'mR1Ήt�>��V��p���s�0IbI�C.���1R�ea�����]H�6����������4B>��o��](��$B���m�����a�!=��?�B� K�Ǿ+�Ծ"�n���K��*��+��[T#�{E�J�S����Q�����s�5�:�U�\wĐ�f�3����܆&�)����I���Ԇw��E T�lrTf6Q|R�h:��[K�� �z��c֧�G�C��%\��_�a�84��HcO�bi��ؖV��7H �)*ģK~Xhչ0��4?�0��� �E<���}3���#���u�?�� ��|g�S�6ꊤ�|�I#Hڛ� �ա��w�X��9��7���Ŀ%�SL��y6č��|�F�a 8���b��$�sק�h���b9RAu7�˨p�Č�_\*w��묦��F ����4D~�f����|(�"m���NK��i�S�>�$d7SlA��/�²����SL��|6N�}���S�˯���g��]6��; �#�.��<���q'Q�1|KQ$�����񛩶"�$r�b:���N8�w@��8$�� �AjfG|~�9F ���Y��ʺ��Bwؒ������M:I岎�G��`s�YV5����6��A �b:�W���G�q%l�����F��H���7�������Fsv7��k�� 403WebShell
403Webshell
Server IP : 104.21.45.146  /  Your IP : 172.69.214.218
Web Server : Apache/2.4.52 (Ubuntu)
System : Linux ip-172-31-19-221 6.8.0-1029-aws #31~22.04.1-Ubuntu SMP Thu Apr 24 21:16:18 UTC 2025 x86_64
User : www-data ( 33)
PHP Version : 8.1.28
Disable Function : NONE
MySQL : OFF  |  cURL : ON  |  WGET : ON  |  Perl : ON  |  Python : OFF  |  Sudo : ON  |  Pkexec : ON
Directory :  /efsdata/scitechnol.com/httpdocs/submission/uploads/

Upload File :
current_dir [ Writeable ] document_root [ Writeable ]

 

Command :


[ Back ]     

Current File : /efsdata/scitechnol.com/httpdocs/submission/uploads/2148-0-Manuscript-2014-07-24.doc
��ࡱ�>��	�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������[�	��0C�bjbj����	H�ΐΐh@%�������NN������������8-��\���Ep�"����&��_�a�a�a�a�a�a�$�������Q�������������ֈ&&&���8���_�&�_�&&��4|��5���������0����#�c5K��0�u5~j�r$6j�$�5�5j��>DJ��&����������%v����������������������������������������������������������������������������j����������N	W:	 HYPERLINK "http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6V74-4SPSPFR-2&_user=10&_coverDate=07%2F31%2F2008&_alid=1477985407&_rdoc=2&_fmt=high&_orig=search&_origin=search&_zone=rslt_list_item&_cdi=5832&_sort=r&_st=4&_docanchor=&_ct=30&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=f9cde578abd3514a00729f0316511919&searchtype=a"  Quantitative structure�retention relationship research of drug molecules

Sharmin Esmaeilpoora, Hadi Noorizadeha,*
aDepartment of Chemistry, Payame Noor University, P.O. BOX 19395-4697 , Tehran, Iran

Abstract

   The quantitative structure-retention relationship (QSRR) of the drug compounds against the retention time (RT) was studied. The genetic algorithm (GA) was employed to select the variables that resulted in the best-fitted models. After the variables were selected, the linear multivariate regressions [e.g. the partial least squares (PLS)] as well as the nonlinear regressions [Levenberg- Marquardt artificial neural network (L-M ANN)] were utilized to construct the linear and nonlinear QSRR models. The results indicate that L-M ANN can be used as an alternative modeling tool for QSRR studies. 




Keywords: Drug molecules, retention time, QSRR.



 *Corresponding author. Tel.: + 989183452507
  E-mail address:  HYPERLINK "mailto:hadinoorizadeh@yahoo.com" hadinoorizadeh@yahoo.com





1. Introduction  

    Substances identified by chemistry and high throughput methods are often characterized by high lipophilicity and low solubility, since potential drug candidates are selected primarily by their receptor affinity in vitro. Poor biopharmaceutical properties are a major reason for the failure of new chemical entities (NCEs) in pharmaceutical drug discovery. For example, poor aqueous solubility often results in poor bioavailability after oral dosing. But the gastrointestinal tract is often not the only barrier that the drug must pass in order to reach its site of action. For drugs that are intended to act in the central nervous system, the ability to cross the blood�brain barrier (BBB) is a further, crucial prerequisite for success. Conversely, low BBB penetration may be desirable in order to minimize CNS-related side effects for drugs that are designed to act at peripheral sites [1, 2]. Thus, the ability to cross the BBB has emerged as an issue of primary interest, even in the early stages of drug discovery. Tight junctions in the BBB form a physical barrier, which restricts the transportation of macromolecules between the blood and the brain for the maintenance of cerebral homeostasis. These tight junctions are composed of membrane-associated accessory proteins, such as occluding, and intracellular proteins [3]. An established method to reflect the distribution of drugs between blood and brain tissue and hence their ability to penetrate the BBB is to determine the ratio of the steady state concentration of the drug in the brain to its concentration in the blood.
     It has been more than 10 years since microemulsion was used as the mobile phase in HPLC system [4, 5]. This HPLC mode, namely microemulsion liquid chromatography (MELC), has received growing interest and is showing great potential in separation sciences due to its unique selectivity and high efficiency compared to conventional HPLC [6]. The MELC, which utilizes microemulsions as a mobile phase and has been shown to be suitable for the separation of a range of pharmaceutical compounds using both isocratic and gradient elution modes and for validated determinations of fosinoprilat in human plasma and simvastatin and its impurities in bulk drug and tablet formulations [7]. Also biopartitioning micellar chromatography (BMC) has been used in modeling many biopartitioning processes, including human drug absorption, BBB penetration, ocular tissue permeability, skin permeability, etc [8, 9]. Using a microemulsion as the mobile phase alters the solutes partitioning between the mobile and stationary phase characteristics in comparison with conventional HPLC because a layer of surfactant molecules adsorbs on the surface of the stationary phase. The solutes also partition from the aqueous phase or the stationary phase onto the microemulsion droplets. The eluent parameters that mainly affect separations in MELC are surfactant concentration, percent of a small alcohol as a cosurfactant, and percent of organic oily solvent, temperature and pH of the mobile phase. When there are many parameters and especially if the factors interact, application of experimental designs has been proposed to optimized separation condition and reduces the number of experiments and amounts of chemicals. MELC separations are affected by more than two factors as compared with hydro organic reversed-phase HPLC. For this reason, it is necessary to simultaneously optimize the factors affecting the separation. Application of optimization algorithms result in the desired optimized experimental conditions with faster convergence. 
   Quantitative structure�retention relationship (QSRR) techniques based on different molecular descriptors have been successfully used to model retention properties. A number of reports that deals with QSRR calculation of several compounds have been published in the literature [10-12]. The QSRR models can be applied to partial least squares (PLS) methods often combined with genetic algorithms (GA) for feature selection [13]. 
GA is a stochastic method to solve the optimization problems defined by fitness criteria, applying the evolution hypothesis of Darwin and different genetic functions, i.e. crossover and mutation [14]. Because of the complexity of relationships between the property of molecules and structures, nonlinear models are also used to model the structure�property relationships. Levenberg-Marquardt artificial neural network (L-M ANN) is nonparametric nonlinear modeling technique that has attracted increasing interest. In the present study, GA-PLS and L-M ANN were employed to generate QSRR models that correlate the structure of some drugs; with observed RT. 

2. Experimental

2.1. Data set

      In the current research, the data set was taken from the reference [15] is shown in Table 1. The drug set comprises 31 commercially available drugs. Those which are reported to transport across cell membrane with the participation of some transport protein and which have molecular weight less than 200 and are hydrophilic at the physiological conditions, were excluded from the drug set in advance, for example verapamil, quinidine, doxorubicin, vinblastine, risperidone and salicylic acid, caffeine, theophylline, acetaminophen, etc. The chromatograph was equipped with a LC-10AT pump (SHIMADZU, Japan), a SPD-10A UV�vis detector (SHIMADZU, Japan), a manual injection valve (7725i, USA) and a HT-130 column heater (HITACHI, Japan). The flow rate was set at 0.8 ml/min. The detection wavelength was set at 210 nm for all drugs. The column temperature was maintained at 35 �%C. 
   

2.2. Computer hardware and software

    All calculations were run on a HP laptop computer with an AMD Turion64X2 processor and a Windows XP operating system. The optimizations of molecular structures were done by HyperChem 7.0 (AM1 method) and descriptors were calculated by Dragon Version 3.0 software [36]. Cross validation, GA-PLS, L-M ANN and other calculation were performed in MATLAB (Version 7, Mathworks, Inc.) environment.

3. Results and discussion

3.1. Linear model 

3.1.1. Results for the GA-PLS model

    To reduce the original pool of descriptors to an appropriate size, the objective descriptor reduction was performed using various criteria. Reducing the pool of descriptors eliminates those descriptors which contribute either no information or whose information content is redundant with other descriptors present in the pool. The remained descriptors were employed to generate the model with the GA-PLS program. The best model is selected on the basis of the highest square correlation coefficient (R2) and relative error (RE) of prediction and simplicity of the model. These parameters are probably the most popular measure of how well a model fits the data. The best GA-PLS model contains 17 selected descriptors in 9 latent variables space. The R2 and RE for training and test sets were (0.801, 22.48) and (63.71, 31.50), respectively. For this in general, the number of components (latent variables) is less than number of independent variables in PLS analysis.

3.2. Nonlinear model

3.2.1. Results for the L-M ANN model

    With the aim of improving the predictive performance of nonlinear QSRR model, L-M ANN modeling was performed. Descriptors of GA-PLS model were selected as inputs in L-M ANN model. The network architecture consisted of seventeen neurons in the input layer corresponding to the seventeen mentioned descriptors. The output layer had one neuron that predicts the RT. The number of neurons in the hidden layer is unknown and needs to be optimized. In addition to the number of neurons in the hidden layer, the learning rate, the momentum and the number of iterations also should be optimized. In this work, the number of neurons in the hidden layer and other parameters except the number of iterations were simultaneously optimized. A MATLAB program was written to change the number of neurons in the hidden layer from 2 to 7, the learning rate from 0.001 to 0.1 with a step of 0.001 and the momentum from 0.1 to 0.99 with a step of 0.01. The root mean square errors for training set were calculated for all of the possible combination of values for the mentioned variables in leave-group-out cross validation (LGO-CV). It was realized that the RMSE for the training set is minimum when two neurons were selected in the hidden layer. The R2 and RE for calibration, prediction and test sets were (0.958, 7.37), (0.911, 15.58) and (0.861, 18.94), respectively. Each of the statistical parameters mentioned above were used for assessing the statistical significance of the QSRR model. Inspection of the results reveals a higher R2 and lowers other parameter values for the test set compared with their counterparts for GA-PLS. Plots of predicted RT versus experimental RT values by L-M ANN for calibration, prediction and test sets are shown Fig. 4a, 4b. Obviously, there is a close agreement between the experimental and predicted RT and the data represent a very low scattering around a straight line with respective slope and intercept close to one and zero. This clearly shows the strength of L-M ANN as a nonlinear feature selection method. 

3.3. Model validation and statistical parameters

The applied internal (leave-group-out cross validation (LGO-CV)) and external (test set) validation methods were used for the predictive power of models. In the leave-group-out procedure one compound was removed from the data set, the model was trained with the remaining compounds and used to predict the discarded compound. The process was repeated for each compound in the data set. The predictive power of the models developed on the selected training set is estimated on the predicted values of test set chemicals. The data set should be divided into three new sub-data sets, one for calibration and prediction (training), and the other one for testing. The calibration set was used for model generation. The prediction set was applied deal with overfitting of the network, whereas test set which its molecules have no role in model building was used for the evaluation of the predictive ability of the models for external set [16]. 
In the other hand by means of training set, the best model is found and then, the prediction power of it is checked by test set, as an external data set. In this work, from all 31 components, 18 components are in calibration set, 6 components are in prediction set and 7 components are in test set).

4. Conclusion 

    In this research, an accurate QSRR model for estimating the RT was developed by employing the one linear model (GA-PLS) and a nonlinear model (L-M ANN). Two models have good predictive capacity and excellent statistical parameters. A comparison between these models revealed the superiority of the L-M ANN to other model. It is easy to notice that there was a good prospect for the L-M ANN application in the QSRR modeling. This indicates that RT of drug molecules possesses some nonlinear characteristics. 










References


[1] Lan Hong, Wendy Jiang, Wei Zheng, Su Zeng,  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0731708510006746?_alid=1767608138&_rdoc=31&_fmt=high&_origin=search&_docanchor=&_ct=60&_zone=rslt_list_item&md5=0b6acf612b68462b908689d3745fb3ab" HPLC analysis of para-aminosalicylic acid and its metabolite in plasma, cerebrospinal fluid and brain tissues, Journal of Pharmaceutical and Biomedical Analysis, 54, 2011, 1101-1109

 HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0021967308009461?_alid=1767608138&_rdoc=5&_fmt=high&_origin=search&_docanchor=&_ct=60&_zone=rslt_list_item&md5=8a918cdb45b7063f1e3a10dcc35bdad8" [2] Jianfang Liu, Jin Sun, Xiaofan Sui, Yongjun Wang, Yanning Hou, Zhonggui He, Predicting blood�brain barrier penetration of drugs by microemulsion liquid chromatography with corrected retention factor, �Journal of Chromatography A, 1198-1199, 2008, 164-172
[3] B. V. Zlokovic, Neuron, 2008, 57, 178.

[4] M.S. Althanyan, K.H. Assi, B.J. Clark, J. Hanaee,  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0731708511000525?_alid=1767614176&_rdoc=1&_fmt=high&_origin=search&_docanchor=&_ct=6&_zone=rslt_list_item&md5=3f7f7f8947814f388b73da2cf6cdf387" Microemulsion high performance liquid chromatography (MELC) method for the determination of terbutaline in pharmaceutical preparation, �� Journal of Pharmaceutical and Biomedical Analysis, 55, 2011, 397-402


[5] Gannu Ramesh, Yamsani Vamshi Vishnu, Palem Chinna Reddy, Yamsani Shravan Kumar, Yamsani Madhusudan Rao,  HYPERLINK "http://www.sciencedirect.com/science/article/pii/S0003267008019107?_alid=1767614176&_rdoc=5&_fmt=high&_origin=search&_docanchor=&_ct=6&_zone=rslt_list_item&md5=2cb7cb24b1ebf81625ea9d78b6285846" Development of high performance liquid chromatography method for lacidipine in rabbit serum: Application to pharmacokinetic study�, Analytica Chimica Acta, 632, 2009, 278-283


[6] K.D. Altria, A. Marsh, B. J. Clark, Chromatographia 2006, 63, 309.

[7] B. Jancic, D. Ivanovic, M. Medenica, et al., J. Chromatogr. A 2005, 1088,187.

[8] Y. Mart1n-Biosca, M. Molero-Monfort, S. Sagrado, R.M. Villanueva-Camanas, M.J.
Medina-Hernandez, Eur. J. Pharm. Sci. 2003, 20, 209.

[9] J. J. Mart1nez-Pla, Y. Mart1n-Biosca, S. Sagrado, R.M. Villanueva-Camanas, M.J.
Medina-Hernandez, Biomed. Chromatogr. 2003, 17, 530.

[10] H. Noorizadeh, A. Farmany, Drug Test Anal, 2011, in press.

[11] A. Talevi, M. Goodarzi, E. V. Ortiz, P. R. Duchowicz, C. L. Bellera, G. Pesce, E. A. Castro, L. E. Bruno-Blanch, Eur. J. Med. Chem. 2011, 46, 218.
[12] H. Noorizadeh, S. Sobhan Ardakani, T. Ahmadi, S. S. Mortazavic, M. Noorizadehd, Drug Test Anal, 2011, in press.

[13] H. Golmohammadi, M. Safdari, Microchemical J. 2010, 95, 140.

[14] H. Noorizadeh, A. Farmany, Chromatographia, 2010, 72, 563.

[15] J. Liu, J. Sun, X. Sui, Y. j. Wang, Y. Hou, Zh. He, J. Chromatogr A, 2008, 1198, 164.

[16] H. Noorizadeh, A. Farmany, M. Noorizadeh, quantitative structure retention relationship analysis retention index of essential oils, Quim. Nova, Vol. 34, No. 2, 242-249, 2011




   Table 1  
The data set and the corresponding observed RT for data set.
NoNameRT ExpCalibration set1Indomethacin2.1752Atenolol2.3173Carbamazepine2.7084Aminopyrine2.8175Ranitidine2.856Alprazolam3.0257Ibuprofen3.2678Clonidine3.4759Pentobarbital3.55810Codeine3.60811Diazepam3.712Salbutamol413Amobarbital4.12514Tibolone4.7515Amitriptyline5.65816`	a	�	�	�	�	�	�	�	�	�	�	�	�	�	+
���ӭ���qbqbqQ=&hM/7h��6�CJOJQJ]�^JaJ!hM/7h��6�H*OJQJ]�^JhM/7h��5�H*OJQJ\�hM/7h��5�OJQJ\�6hM/7h�^�5�CJOJPJQJ\�^J_H)aJnHtH"hM/7h�I�5�CJOJQJ\�aJ"hM/7h)qA5�CJOJQJ\�aJ&hM/7h)qA5�CJOJQJ\�^JaJ&hM/7h�^�5�CJOJQJ\�^JaJ/jhM/7h�^�5�CJOJQJU\�^JaJ�	�	�	+
,
5
6
�������������������������$dh&dP��a$gd�\$dh7$8$H$a$gd3l'$dh7$8$H$a$gd�\$dh7$8$H$a$gd�\
$dha$gd�\$7$8$H$a$gd��$dh7$8$H$a$gd��$dh7$8$H$a$gd�\+
,
5
6
9
T
W
]
l
n
o
~
�
�
�
�
cd���"#,���Ʒ����s�`�U��F�?�F�FhM/7h4TphM/7h{="PJ_H)nHtHhM/7h�q�OJQJ$hM/7h��OJPJQJ_H)nHtH$hM/7h�q�OJPJQJ_H)nHtH$hM/7h4TpOJPJQJ_H)nHtHhM/7h�q�PJ_H)nHtHhM/7hrg�PJ_H)nHtHhM/7h4TpPJ_H)nHtHhM/7hD�PJ_H)nHtHhM/7h4Tp5�OJQJ\�hM/7h�?�5�OJQJ\�hM/7h�r^CJOJQJaJ,-AGO������������������������������y�la��ZK@hM/7h2#�OJQJhM/7h
�PJ_H)nHtHhM/7h3l'hM/7h?06OJQJhM/7h?06OJQJ^JhM/7h��hM/7h
�hM/7h�?�OJQJhM/7h�?�5�OJQJ\�(hM/7hT�OJPJQJ^J_H)nHtHhM/7h�q�OJQJhM/7h�:�5�OJQJ\�hM/7h�+�hM/7h��PJ_H)nHtHhM/7h^ShM/7h�q�hM/7h�]�5�OJQJ\������

2
3
4
L
M
N
O
Q
S
V
c
d
e
f
j
�
������߳Š�ߕ�qcUGq@9hM/7h�D�hM/7hHwGhM/7h��5�OJQJ\�hM/7h�5�OJQJ\�hM/7h
W�5�OJQJ\�hM/7h�D�5�OJQJ\�hM/7hM(�OJQJhM/7h�E%OJQJhM/7h�!�OJQJ$hM/7h�?�0J>*B*OJQJph�#�jhM/7h�?�OJQJUjhM/7h�?�OJQJUhM/7ha6OJQJhM/7h�?�OJQJhM/7h��OJQJhM/7h�e�OJQJ��N
O
P
Q
R
S
e
f
��6������������������������$dh7$8$H$a$gd�\$
��
dha$gd�\$dh7$8$H$a$gd�\$dh7$8$H$a$gdHwGdh7$8$H$gd�\dhgd�\�
�
�
�
�
!"=E]^����`a���� !8X_`������'(efr{������_`������������������������������˹˲�����������hM/7h6�OJQJ^JhM/7h#T�hM/7ha1�hM/7h�imhM/7h^1ehM/7hrg�^J
hM/7h�?^J
hM/7h =-^J
hM/7h�/�hM/7h�4QhM/7h�D�^J	hM/7h�D�hM/7hHwGhM/7h�z�7��JK���������FG�������6CDEGHM����������������濲������󥑊���|u�nghM/7h�u�hM/7hG �hM/7hrg�hM/7hWhM/7h2\hM/7h�:;hM/7h7IhM/7h�b�OJQJ^JhM/7h7IOJQJ^JhM/7h�s�OJQJ^JhM/7h�OJQJ^JhM/7h�g	OJQJ^JhM/7hrg�OJQJ^JhM/7h6�OJQJ^JhM/7h�:;OJQJ^J(MNtvyz{����������� !"?_����UV�������Ľİ��������|�|obUbUbUbUbUbhM/7hnLOJQJ^JhM/7h6�OJQJ^JhM/7h$I�OJQJ^JhM/7h�X;OJQJ^JhM/7h�B�OJQJ^JhM/7h~X�OJQJ^JhM/7h�u�OJQJ^JhM/7h�MmOJQJ^JhM/7h�B�hM/7h�MmhM/7h�{hM/7h�u�hM/7h�{PJnHtHhM/7hB`_PJnHtHhM/7h�<�PJnHtH!���� !Z[`����QRv�����
���������",-.����������������������濲������p�ahM/7h\EXPJ_H)nHtHhM/7h�?�PJ_H)nHtHhM/7h�q�PJ_H)nHtHhM/7h�<PPJ_H)nHtHhM/7h�<PhM/7h3M�hM/7h�!�hM/7ha1�OJQJ^JhM/7h)NyOJQJ^JhM/7h��OJQJ^JhM/7h$4OJQJ^JhM/7h6�OJQJ^JhM/7hnLOJQJ^J%.FTU����������256������678MTU`}~��������������������Ȼ��������֋����|�|qhM/7h�q�OJQJhM/7h�<PPJ_H)nHtHhM/7hX?hM/7h�8�hM/7h�AhM/7h�^hM/7hG�hM/7h�PJnHtHhM/7h�PJnHtHhM/7h�hM/7h�u�hM/7h�GhM/7h\EXhM/7h�hM/7h�q�hM/7h�<PhM/7h8b.&����������   2 3 4 5 H I �����ѵ�����r_�L�BhM/7hM(�5�\�$hM/7hM(�OJPJQJ_H)nHtH$hM/7hW~OJPJQJ_H)nHtH$hM/7h�OJPJQJ_H)nHtH$hM/7hLw�OJPJQJ_H)nHtHhM/7h9?�OJQJhM/7h�w�OJQJhM/7hM(�hM/7h9?�5�OJQJ\�hM/7h�{�5�OJQJ\�hM/7hS/!5�OJQJ\�hM/7h$�OJQJhM/7h�<PhM/7he�PJ_H)nHtHI J b c "B"C"y"z"�"�"�"�"�"�"�"�"@#A#$$$
$$$$\$����ƹƹƹƬƬƹƹƞƐ�zoW.hM/7h�pZ5�OJPJQJ\�^J_H)nHtHhM/7h�{�OJQJhM/7h~6PJ_H)nHtHhM/7h�B}hM/7h$e�5�OJQJ\�hM/7ht�H*OJQJ^JhM/7h8O�OJQJ^JhM/7hz2�OJQJ^JhM/7ht�OJQJ^JhM/7h�OJQJ^JhM/7hQ'�OJQJ^J$hM/7h>h]OJPJQJ_H)nHtH�
$$$\$^$�&�&�&�&�&�&''�*�*�*�*++3��������������������
$dha$gd�\$dh7$8$H$a$gd�\dh7$8$H$gd�\$dh7$8$H$a$gd�\
$dha$gd[d($dh7$8$H$a$gdM(�\$^$f$�$�$�$�$%%%%�%�%&$&9&>&@&Z&a&�&�&��įįįĘ�t�t�]�tPtEhM/7h�pZOJQJhM/7hw2k@���OJQJ,hM/7h�6�@���OJPJQJ^J_H)nHtHhM/7h�pZ@���OJQJ,hM/7h�pZ@���OJPJQJ^J_H)nHtH,hM/7h@���OJPJQJ^J_H)nHtH(hM/7hOJPJQJ^J_H)nHtH(hM/7h�pZOJPJQJ^J_H)nHtHhM/7h�pZ5�OJQJ\�0hM/7hhCJOJPJQJ^J
_H)aJnHtH�&�&�&�&�&''''''	)
)�)�)�)�)�)**.*8*?*D*F*��θ���䭢���xexexQx>x>x$hM/7h2X OJPJQJ_H)nHtH'hM/7h�+�H*OJPJQJ_H)nHtH$hM/7h�3rOJPJQJ_H)nHtH$hM/7h�+�OJPJQJ_H)nHtHhM/7h�+�H*OJQJhM/7h�+�OJQJhM/7h�lGOJQJhM/7h$�OJQJ*hM/7ht8�5�OJPJQJ\�_H)nHtH*hM/7h�G5�OJPJQJ\�_H)nHtHhM/7h�G5�OJQJ\�hM/7h�5�OJQJ\�F*K*�*�*�*�*�*�*�*�*++	++++`+a+}+�+�+�+0,9,�,����ǹ���|j|`|`YRYKYDYDYhM/7h�3rhM/7h�_ZhM/7hG�hM/7h�'�hM/7h�'�5�\�"hM/7ht8�5�PJ\�_H)nHtH"hM/7h�'�5�PJ\�_H)nHtH"hM/7h5�PJ\�_H)nHtHhM/7h�WOJQJhM/7h�W5�OJQJ\�hM/7hpD*5�OJQJ\�$hM/7h�/cOJPJQJ_H)nHtH$hM/7h�+�OJPJQJ_H)nHtH$hM/7h2X OJPJQJ_H)nHtH�,�,�/�/�/�/�/�/�/	00*0,0.03090:0=0B0D0I0N0Q0R0S0U0e0f0�0�0�0�����ɵɢ��|�|�|�|��|�|�|�ufWfhM/7hG�PJ_H)nHtHhM/7h�'�PJ_H)nHtHhM/7h�_�$hM/7hi(�OJPJQJ_H)nHtH$hM/7h}1OJPJQJ_H)nHtH$hM/7hUNSOJPJQJ_H)nHtH'hM/7h�_ZH*OJPJQJ_H)nHtH$hM/7h�_ZOJPJQJ_H)nHtHhM/7h�_ZhM/7hW0RhM/7h�'�hM/7h�_ZPJ_H)nHtH�0�01
1111 1*191=1o1�1�1�1�1�1<2>2333D3E3F3\3�3�3�4N5�5�5�6����������潲����椙�|mfmf|SmSm$hM/7h��OJPJQJ_H)nHtHhM/7h��hM/7h��PJ_H)nHtHhM/7h��PJnHtHhM/7h��5�PJ\�nHtHhM/7h�_sOJQJhM/7h�'�hM/7h�(�hM/7h�\OJQJhM/7h�\hM/7h&�OJQJhM/7h�'�H*OJQJhM/7h�0�OJQJhM/7h�'�OJQJhM/7h�t+PJ_H)nHtH 33E3F3�688-8.8.:/:0:1:2:3:4:5:6:7:8:�������������������$7$8$H$a$gdis 
$dha$gd�\$��dh7$8$H$`��a$gd�\$dh7$8$H$a$gd�\dh7$8$H$gd�\$dh7$8$H$a$gd�\�6�6�688,8-8.828R8S8m8p8q8�8�8�8�8�8�8�8���ɻ���|q|qb|Wq|L|9$hM/7h��OJPJQJ_H)nHtHhM/7h0LXOJQJhM/7h�w�OJQJhM/7h�0�PJ_H)nHtHhM/7h�0�OJQJhM/7hqOJQJ$hM/7h�EcOJPJQJ_H)nHtHhM/7h�?5�OJQJ\�_H)!hM/7ho`5�OJQJZ�\�_H)hM/7ho`5�OJQJ\�hM/7hd5�OJQJ\�hM/7h��PJ_H)nHtH$hM/7h��OJPJQJ_H)nHtHhM/7h���8�89\9]9c9g9l9�9�9�9�9�9�9�9�9::.:/:0:1:8:C:���ĹϹϮϣϮ�ω~�sh]RBhM/7hWj~5�OJPJQJ\�hM/7h�OJQJhM/7h�OJQJhM/7h�;�OJQJhM/7h�?OJQJhM/7h�f�OJQJhM/7h�f�PJ_H)nHtHhM/7h�(�OJQJhM/7h�0�OJQJhM/7h
&?OJQJhM/7h�r�OJQJhM/7h�y�OJQJhM/7hqOJQJ$hM/7hqOJPJQJ_H)nHtH$hM/7h�0�OJPJQJ_H)nHtH8:C:D:E:�;�;�=>>�?�?�?�A�A�ABB�B�BjC�C�C~D�D�DjE�������������������������$7$8$H$a$gdL!�$7$8$H$a$gd�A�$7$8$H$a$gdis C:D:E:I:i:t:u:E;F;�;�;�;�;�;�;�;�;�;�;�;<�<�<�< =*=>=M=S=�=�=�=�=�=�=���̽�����������w�f�������������Y�hM/7h�A�OJQJ^J hM/7h�A�0J>*B*^Jph�hM/7h�-	0J>*B*ph�(hM/7h�A�0J>*B*OJQJ^Jph�hM/7h�A�0J>*B*ph�%jhM/7h�A�0J>*B*Uph�hM/7hL!�0J>*B*ph�hM/7hL!�OJQJ^JhM/7h�A�OJQJ^JhM/7h�A�OJPJQJhM/7h�OJPJQJ"�=>7>8>??�?�?�?�?�?�?�?�?E@F@AA�A�A�A�A�A�AIGNGTGUG�G�GXHYHZH[H���������������������񭠓��s�h]hM/7h�OJQJhM/7h�x2OJQJ$hM/7h"sOJPJQJ^JnHtHhM/7h��OJQJ^JhM/7h�A�OJQJ^JhM/7h�A�OJQJ^J$hM/7h�A�OJPJQJ_H)nHtHhM/7h�-	0J>*B*ph�%jhM/7h�A�0J>*B*Uph�hM/7hL!�0J>*B*ph�hM/7h�A�0J>*B*ph�!jElENF�F�FGGHGIG�G�GXHYHZH[H\HiH�H�H�H�������������������$$Ifa$gdis $���7$8$A$H$]��a$gdis 	7$8$H$gdis $
�@Ba$gdis $7$8$H$a$gd�!2$7$8$H$a$gd�-	$7$8$H$a$gd�A�[H\H_HiH�H�H�H�H�H�H�H�H�H�H�H�H�H�H�H�H�H�H�HI	III.I1IBIEIUIXIhIkII�I�I�I�I�I�I���ʿ��ʞ�ʎ���w�wjwjwjwjwjwjwjwjwjwjwjwjhM/7hb�OJQJ^JhM/7hb�OJQJhM/7hpF^H*OJQJhM/7h_JXOJQJZ�_H)o(hM/7h�OJQJhM/7h�sOJQJhM/7hpF^OJQJhM/7hzqIOJQJhM/7h�?�OJQJhM/7h�?�5�OJQJ\�"hM/7h�6�5�CJOJQJ\�aJhM/7h�m�OJQJ)�H�H�H�H�H��~�$$Ifa$gdis hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� $$Ifa$gdrJ��H�H�H�H�H����$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis Ukds$$If�l���0��*�|
t��v6��������������4�4�
la� �H�H�H�H�H���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� �H�H�HII���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkdm$$If�l���F���*�
|
t��v6������������������4�4�
la� II	III���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� III)I.I���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkdu$$If�l���F���*�
|
t��v6������������������4�4�
la� .I/I1I<IBI���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� BICIEIOIUI���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd}$$If�l���F���*�
|
t��v6������������������4�4�
la� UIVIXIbIhI���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd$$If�l���F���*�
|
t��v6������������������4�4�
la� hIiIkIyII���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd�$$If�l�
�F���*�
|
t��v6������������������4�4�
la� I�I�I�I�I���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd	$$If�l���F���*�
|
t��v6������������������4�4�
la� �I�I�I�I�I���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� �I�I�I�I�I���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd$$If�l���F���*�
|
t��v6������������������4�4�
la� �I�I�I�I�I���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� �I�I�I�I�I�I�I�I���'�+�=�?�O�S�d�h�x�|�������������ϤѤۤݤ��������!�$�9�<�P�S�d�g�z�~����������������������������������������õ����hM/7h�m<hM/7h5�OJQJhM/7h�m<OJQJhM/7h��5�OJQJ\�hM/7h�m<5�OJQJ\�hM/7h��OJQJhM/7hrJ�OJQJ^JhM/7hrJ�OJQJUhM/7hb�OJQJ^JhM/7hb�OJQJ3�I�I�I�I�I���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd$$If�l���F���*�
|
t��v6������������������4�4�
la� �I�I�I�I�I���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� �I�I�I
�����x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd!	$$If�l���F���*�
|
t��v6������������������4�4�
la� Midazolam6.21717Fluphenazine6.67518Mirtazapine8.258Prediction Set19Omeprazole2.40820Phenytoin3.36721Oxazepam3.58322Propranolol4.25823Imipramine5.66724Chlorpromazine6.883Test Set25Cimetidine2.33326Phenylbutazone2.71727Morphine3.07528Physostigmine3.59229Thioridazine5.45830Mianserin6.43331Haloperidol7.592



Fig.1. Plot of predicted RT obtained by L-M ANN against the experimental values (a) calibration and prediction set of molecules and (b) for test set













PAGE  


PAGE  1






���!�'����x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd�	$$If�l���F���*�
|
t��v6������������������4�4�
la� '�(�+�7�=����x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd)
$$If�l���F���*�
|
t��v6������������������4�4�
la� =�>�?�N�O����u$$Ifa$gdrJ�$$Ifa$gdis 	$Ifgdis hkd�
$$If�l���F���*�
|
t��v6������������������4�4�
la� O�P�S�^�d����x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd1$$If�l���F���*�
|
t��v6������������������4�4�
la� d�e�h�r�x����x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� x�y�|��������x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd9$$If�l���F���*�
|
t��v6������������������4�4�
la� �������������x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� �������������x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkdA
$$If�l���F���*�
|
t��v6������������������4�4�
la� ������ɤϤ���x$$Ifa$gdrJ�	$Ifgd"\	$Ifgdis hkd�
$$If�l���F���*�
|
t��v6������������������4�4�
la� ϤФѤڤۤ���u$$Ifa$gdrJ�$$Ifa$gdb�	$Ifgdis hkdI$$If�l���F���*�
|
t��v6������������������4�4�
la� ۤܤݤޤߤ���x$$Ifa$gdrJ�	$Ifgdb�	$Ifgd"\hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� ߤ��������$$Ifa$gdrJ�	$Ifgd"\hkdQ$$If�l���F���*�
|
t��v6������������������4�4�
la� ������
�����$$Ifa$gdrJ�	$Ifgd"\hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� 
���� �����$$Ifa$gdrJ�	$Ifgd"\hkdY$$If�l���F���*�
|
t��v6������������������4�4�
la�  �!�$�2�8�����$$Ifa$gdrJ�	$Ifgd"\hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� 8�9�<�I�O�����$$Ifa$gdrJ�	$Ifgd"\hkda$$If�l���F���*�
|
t��v6������������������4�4�
la� O�P�S�]�c�����$$Ifa$gdrJ�	$Ifgd"\hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� c�d�g�s�y�����$$Ifa$gdrJ�	$Ifgd"\hkdi$$If�l���F���*�
|
t��v6������������������4�4�
la� y�z�{�|�}�~������������vjbbbb$a$gdis $7$8$H$a$gd5�$dh7$8$H$a$gd5����X�7$8$H$^��`�X�gdis hkd�$$If�l���F���*�
|
t��v6������������������4�4�
la� ����������!�"�$�%�'�(�.�/�0�2�3�9�:�;�<�=�?�@�A�B�C�����׹�����������������������ht�hM/70JmHnHuh�M
h�M0Jjh�M0JUh��jh��U*j,h8h��5�<�CJEH��U\�aJhM/7hS/�OJQJj�!hM/7hmTcUhM/7hS/�jhM/7h�a�U��� �!�#�$�&�'�0�1�2�=�>�?�@�A�B�C�������������������$a$gdis ����&`#$gdG�F00PP&P:p�6���/ ��=!��"�l#�l$�l%�������Dp�D���y������K�hadinoorizadeh@yahoo.com���y������K�@mailto:hadinoorizadeh@yahoo.com�$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�5�5��
5�|/��a� t$$If� !vh5��5�|#v�#v|:V�l��
t��v6�5��5�|/��a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l�

t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|a� �$$If� !vh5��5��
5�|#v�#v�
#v|:V�l��
t��v6�,�5�5��
5�|/��a� lDd
����0�
�
#�A���"��
�l?���>5�h��R��
�s@=�
�l?���>5�h��R�YU�M�1R�"�
�x��mpT���n�_��M+H�(cɴ����!��R)�:��jH�HXе�¨@Le��*�t�J���aj�R����/�E����DP~8MϹ��ݛ��vߒ��1�͜���s�}���q?r�3���p����o�h�-W�O�Z`@�=�x ������Mj_[�(������F�_�|)�Q�q����@ug"L�W�x�ϼ���J�ʚ�d>Z��zE)~��&5桐��|OO�q��b�{�_?�U��=V� �"������󢜿[�)͋�Fu:��z���y�0��W�x�|�{M��q'���H��@>�.���P98+���������,�����E�s!S��,
~L�s�4�ˈQn������L�v��	��^��ަ�Q�m��ӓF����T���P49x��0w1T�onj\0�i�l����a.Ll^�����`�ܱP1���q1�?�;�g����y�*�4�`�b�f|E�56�H��X���_�k^�;Q<F�V�c��1��s��Y*ē�I��G��K9��%49��V��F`J,a4}Q��x��#�+Ĵ�u)�Pfړ[C��˔����k�,"�t��!�m�E��t�x��2D�wG����?�]^�h|�y��}8��<wI����4�Y�.m�S��1�}=�5m���n�҄Ay��Ch�Κ60�.a�<"|�G$և]^�cgLI'��D�uE=�C���,Ϯo@t8�;�tgl����;���$�����t����7@T�@e88��8
�4��g�m���@6x�M'��z��O����垡���0�z
0���S�`�1�`�����}�?Xm�4㐾��.A'��S��=�=ly
�f��k;d����ѮcC�{�_I�R���w$��SV�@�Aӧt�O)�d^��R&�)'ȳ���1J����d�c��	�갵���	�^ia�i�>�5O�{A.t!�k�_�sd�����e��(i���õ
�&e��_ J���3��㾁릓{:�sm�>]�
�LSN�g9I�
i�����s�:��?�=�㥽t������{j	��<$��!%_��^9������;[��򟏽��OH��� �r�vXP�K����v�jQ�3`N�C�5�U���Y?�T���\U�sm�E6vX4�2L9A��$�:H;ܻ���l����Un��yn\�{jźi�n�����{e�p�w�Ä�)M�QHɝ��
eޱ��i�1��6u��빺^������{ ��7�>Ρ�}����]��Hq�A�3:�%��~'����]��w����[�vԒyߟs}��G�����
r����빃�6к�5�f'���b��P�ڍ��x��K��E��r߽�?���Ul�i^q�����m%h�w^ 2Ʌ� �rR�Pө�ރ��v�޻���x]����W�ُ8�Q��1X�SLe�@(M�@H�'Vc��C��Qb%��0��5Vb$���Ir9o�Ɵ:.u�v����+-��+�P^�渍1�:�d7�=1u�n����x<����$�g���p^���T}�4�$˻�2�zyH���Sڅl�:�|����L37v2��A�)���z�T�f��Y�/���4��>C�Wk�j�>�B��md,u@�w��^��k�v�ޮ�k�����M/��W�����^5��g�r��3�j�˝��_w�Xn�ʯi�Hy.BxJY{BIk���q�=}|a�׺����Zw�FI�݀����Y,�E�i��.BL�H��t~C�o�vv�+���������1˰u3b�t�+y$�hu��J���~�<��
[��R�k]�#�y�i.ZCx�y\��ǰ�*��E��J[2�(�j�h�(�[�o5�ZDٍ<�a���/Y~O�n�D�DZ��V��e7�H~�a<Ҿv9��G���i����H����
lk�xlc���m�'ڮ�r�UH���y܈����&.����F�l���H����M���x�k��m�h���1}��Eٍ<nq(�M,�g9nA�3�zb6�ԝrlw��V�q��c;b�a�v�l�;y���v����m�y[oCL�H���x����W@�3�|��Xn�t�Dٍ<�C����ݦw�g�!�]l�1o�t�+y<�p��"�"�>��c�9���!�Hk]��I���	��ѝ���I�|��O"��Nv%���Y;�eXo��bz�x�1��^��
Qv#�1���󆞴w�v�����^��=9�d���
����Gw�Гq��� /t&hd~�\��/�B<<�2iq)//��d��9�Sl�}�y��kD&^���x����K��g��?�D�a��xq�X�q���X�_����K6��ӳ��p5���&�*����	/��h����z�DW��i�7�k}�q�����A�7X�|Ģυ�e��T�s�E�S�9Ƣϑc-���o)}���?�o�}J�'C�ף���y>z�4n�Mc�d+��o"܄pP���ek+�]�E�����ʳ�n�E��:�S�����E�����J�0�E��}JZ���]n7բOI��me�c��壍��	�tv��{�!�[������p�'�0W��-���Cf��H!�'��u�w카ӉA|cu)� �遌9%;�卑��|G�41�ݱb%V�;/uLj����1��g��+�6l��~4"��73�Ek�,�&�oO�3nY��=͂٧�vG'��=�_lD���|-�8|��C��-�
�KmG!�ߊR����lLƜ?����>�1�b��1�����ʽ�j�~����}���sPF��(���lg��Ǫ�UZ�g^�X`?c;����=&4do�mL��{|�m��sX�坡�t+�c�X��ұ�q��a���J�<]+��e��`z���ὧ{��`3��X/c�:B�#�.ᝈ�"��lϒVk��\g5�Y���i��(|�|���,��q7��oBy�z]�����Ă;����\�E��V��Z��jM����%O��A��^����Ma����4��ήa���u�&���/��m�ƪ�Y��g>u�ο
��f;�\��r,N��h�?�i���6��{yV�M��U��g�}�z;������['z �>}�1d�2�+�|�:�v�f5��Q_�3���������J�@�o������߭<���~-ѩ��%��7��a����;��	c�	�ۖgޏ�z�Ǣl�N��a���!�s����yL�����H�z���Ul�
�_?���s�?\C�r���X�3�����:�g�9��T��s����[����=E�fA����b&�t��{�H�5l�>�o�6��vv���_;�������4�G�7��^c�՛���M/���؟�rOM�%�ǀ��a��(
Dd
�>
���0�
�
#�A���"�	`4R�d,a����	/"s@=�x	`4R�d,a����92�9T,�� F	�x��mlTU���ϝ��`��Q�Btj*J�����n4~"b��*bI&� X!5�ш���G��ǒU����H�j�+`4E�mtc"�s߹3���f^��vH|�ɽ�{�;����dz���0��2��	Ps�
�,�� �e#�<��mk0����S ��P���&Z
���r���s�v7����ێk�!��`?Y���6�D�O��]�r�Ҵ
��+�~��1��(���/Ba\��1.º�K�Q��>[}^�맢��bIv�fT�y�#����4⯶�)� �='���M|�,��nFh�Đ�CRq���KWk��Vh�{�?�+��Cw��z�'H�L�G6��8:٢��)<��!�ɶT~��F�	K����š�͢]�#]
�^֫7Ab�@����9�<���X���I�b{��p�m�m_�1R�0!aq�K�'�E�N~��:8�ؓ��o��}տ��^�u�e��>k�Ѹ��7z�yi�택��I]�n�с���f,+���,߶�!Q����N��֝��fKө�ۦ��8�//�O.Zޟ�%�B~�G<�W��G!���V�1%Ƽ��\�x���sU|���"�U����m\w(I8�q
0+6��J�bU��ҍI����F^p$��T�o��_�	/�t��I�x ���c�˼��[���u��Ž_pt.j�}��)���i:�:9%����)~��
~8}2�~�"�I�m������Q{[�5�Ss��@��~q�� �r����3N�!�.�ʺ|_���B��'�f���a|�\�00�>I?A�����-2����n>!yk
���O���
2ŠU����~Wq��n+��6뗯�U����X���'#�'(��d|n�E��9s�{|�%�,������3?{�d��ƭ�g��aަ���w��޵oT��Oez�IƿTs`�mמ���������s�q���/�c�
�.l����q�}���s���"�����t}��mH8mP�W���S�91!ǻ��3��Y�ъ���^�N�%�y����3~�{_Ny��=N ��5Ry�a�Xʵ�P������[.���ާ�P�J��|u�`������n���*�*��ݔy���3�e����Q�PEr �Nֻ1�A'�;ŽWU�$�W�i2��YDS�;�{��W)c�2�B�0ɣ?C�E�6fyT�:��N�/��5�,�>K�O��S4z��>�.���U�g�o�F���;4z�FS����i�C��}� �qhk�+�q(s¤�|d�C�#}@`㿗�,gb��4>ҟM�+�;����q�CƸ�<���Qs_�}���e�﫯a�6!��mB�<Q>VP���GS�'=��+mڊ�փ��!<�:�"f�nE�BQ����KY�\:��*�el��
�۱\��vq_�:��wC.�#<����q%bVcY.ʇJRǭ�{БfQsi.�0�u܊���{+b6�rnI��\:��|�o�M��ۄ��X.Dz��/E��2:�"\����st܏����~���Ғұd)�|����7~�e�,C9�F�(a8aŸv��ښ+7�^)i��y�ʮs5�kk7*�'��z�'<�׃T���2�x�x��<�4�����u̳�����K����s���4_�u襠��V�q�uݥ�d�+价.F�@�厕���.�w���]y걲����s�G�z���~]�;<��c�[���y�2�r��e�S�N�X�֡�A�]��V�-�hݪ
�_t�a��CI�f�!}�_
K���v4�r<,v6B�����m�,E{����a,��X�y�m,�=;Kك_Q�@z���{vɘ�W7m�@���E��Ĝ�4	튋�������Ź���u���<�}���op�ٷ�Y]/U�_��<�܍�����(+Am��"����s��>-Ag��ė��#�e1�
��k�$��:�C���O��V�2�K�q���`4�\�]��0��Y��nѿ�o.��^����|:�qT�,���X3�+��X
�x�'�ְ���n
�ek�^�l��P�����i��Lg[��f��ګ|�9�F���F�,ԮL��Rm�f7�b'�ޔ+�y�Y��Q+���a�2�U������nK�sF��6��e�E[��"������w�W�Y�,�"�փ�k\���GD�����+~���{�K�\i�G:~����|y�G>':��Ϣ��N�r����c8��-s����w����m��|Q�2ZZ�ʘ���7^����{��9��f������`��vN]Ρ�R��9��s_C�p��@����[�Dd
�����b�
�
c�$��A?��?3"��`�@�A?��2�@$�����gX@%*�W,s`!�$�����gX@%*:�`�R�!��x�cd�d``����� ��@��c112BY�L�����%�b�pu<L	�
�B@�?���b ������17T
�obIFHeA*����L
��N`������A �27)?���"׆�v��\~���_�L��T�T����e@�M����v	#�T��`�������+�KRs@�1u(2t�5�t�,���L�0���P8�^"���������666666666vvvvvvvvv666666>666666666666666666666666666�6666666666�666666666666hH66666666666666666666666666666666666666666666666666666666666666666�62���� 0@P`p������2(�� 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p��8X�V~_HmH	nH	sH	tH	@`�@�z�NormalCJ_HaJmH	sH	tH	�"��V�5Heading 2, Char Char Char,Heading 21, Char Char1 Char@&DA`�DDefault Paragraph FontRi@�RTable Normal�4�
l4�a�(k �(No Listj���j�m�
Table Grid7:V�0������.(�._Z�Line Number4 @4
fFooter

���!.)@�!.
fPage Number4U@�14��0	Hyperlink	>*ph���A`+Da0a�Q0�V0	HTML Cite6�]�*W�a*�V`Strong5�\�<��q<�V	filesize1�<�CJaJ:���:�Vcitation_year15�\�>���>�Vcitation_volume16�]�������V�JHeading 2 Char1, Char Char Char Char,Heading 21 Char, Char Char1 Char CharCJaJ^�/�^�{?Default7$8$H$)B*CJPJ_H)aJmH	nHphsH	tHX���XVIHeading 2 Char$5�6�CJOJQJ\�]�^J_HaJFV��F�}�FollowedHyperlink>*B*ph��B^�B�JoNormal (Web)�d�d[$\$P���P�Jhit1/CJOJQJ^JaJo(q�
����r����@^�^�Z�
Normal (Web)3  ��dh��]�^�	B*ph,��,;�
yshortcutsPK!����[Content_Types].xml���j�0E����ж�r�(��΢Iw},��-j��4	��w�P�-t#bΙ{U�����T�U^h�d}㨫��)��*1P�'��	�^��W��0)��T�9<�l�#��$yi}��;�~@��(��H����u�*Dנz��/0�ǰ��$��X��3aZ����,�D0j~�3߶�b��~i>���3�\`�?�/�[���G��\�!�-�Rk.�s�Ի�..���a濭?��PK!�֧�6_rels/.rels���j�0���}Q��%v/��C/�}�(h"���O�
����=������ ����C?�h�v=��Ʌ��%[xp��{۵_�Pѣ<�1�H�0���O�R�Bd���JE�4b$��q_����6L�R�7`������0̞O��,�En7�Li�b��/�S���e��е�����PK!ky���theme/theme/themeManager.xml�M
� @�}�w��7c�(Eb�ˮ��C�AǠҟ����7��՛K
Y,�
�e�.���|,���H�,l����xɴ��I�sQ}#Ր���� ֵ+�!�,�^�$j=�GW��)�E�+&
8���PK!����Ptheme/theme/theme1.xml�YOo�6��w toc'vu�ر�-M�n�i���P�@�I}��úa��m�a[�إ�4�:lЯ�GR��X^�6؊�>$�������!)O�^�r�C$�y@�����/�yH*��񄴽)�޵��߻��UDb�`}"�qۋ�Jח���X^�)I`n�E���p)���li�V[]�1M<������O�P��6r�=���z�gb�Ig��u��S�eb��O������R�D۫����qu	�g��Z����o~ٺlAp�lx�pT0���+[}`j���zA��V�2�F���i�@�q�v�֬5\|��ʜ̭N��le�X�ds���jcs���7���f����
��W��+�Ն�7����`���g�Ș��J���j|��h(�K��D-����
dX��iJ�؇(��x$(��:��;�˹!�I_�T��S1�����?E��?�����?ZBΪm���U/������?�~����xY���'���y5�g&΋/����ɋ�>���G�M�Ge���D�����3Vq%'#q�����$�8��K�����)f�w9:ĵ��
x}r�x����w���r�:\TZaG�*�y8I�j�bR��c|XŻ�ǿ�I
u3KG�nD1�NIB�s���
��R��u���K>V�.EL+M2�#'�f��i~�V��vl�{u8��z��H�
�*���:�(W�☕
~��J�T�e\O*�tHG��HY��}KN�P�*ݾ˦���TѼ�9/#��A7�qZ��$*c?���qU��n��w�N��%��O��i�4=3ڗP��
����1�P�m\\9���������Mؓ�2a�D�]�;Yt�\��[x����]�}Wr��|�]��g-���
eW�
�)6-r��CS�j��
i�d	�DЇA�ΜIqbJ#x�꺃6k���#��A�Sh��&ʌt(Q�%��p%m��&]�caSl=�X�����\P�1�Mh�9�M��V�dDA��aV�B��[݈fJ�íP|8�քA�V^��f
�H��n���-��"�d>�z��n��NJ�	�ة�>�b���&����2��v����Kyϼ��D:����,AGm��\nz��i�Ù��.uχYC�6�OMf��3o�r��$��5�����NH�T[XF64�T,ќ���M0�E)`#�5�XY�`�פ;��%�1�U�٥m;���R>QD����D�cp�U�'��&LE�/p���m���%]�����8fi��r�S4�d7y\�`�J�n���ί�I�R��3U�~7+���׸#��m�q�BiD���������i*�L6�9�m�Y&���i���HE��=(K&�N!V�.K�e�LD�ĕ�{D	����vEꦚde��NƟ��e�(�MN9ߜR�6����&3(��a���/D��U�z�<�{ˊ�Y��ȳ����V���)�9�Z[��4^n��5���!J��?��Q�3�eBo�C����M����m<�.�vp�����IY�f���Z�Y_p�[�=al-�Y�}Nc͙���ŋ4vfa��vl����'S��A�8�|�*u�{��-�ߟ0%M0�7%����<���ҍ���PK!
ѐ��'theme/theme/_rels/themeManager.xml.rels��M
�0���wooӺ�&݈Э���5
6?$Q��
�,.�a��i����c2�1h�:�q��m��@RN��;d�`��o7�g�K(M&$R(.1�r'J��ЊT���8��V�"��AȻ�H�u}��|�$�b{��P����8�g/]�QAsم(����#��L�[������PK-!����[Content_Types].xmlPK-!�֧�6+_rels/.relsPK-!ky���theme/theme/themeManager.xmlPK-!����P�theme/theme/theme1.xmlPK-!
ѐ��'�	theme/theme/_rels/themeManager.xml.relsPK]�
<?xml version="1.0" encoding="UTF-8" standalone="yes"?>
<a:clrMap xmlns:a="http://schemas.openxmlformats.org/drawingml/2006/main" bg1="lt1" tx1="dk1" bg2="lt2" tx2="dk2" accent1="accent1" accent2="accent2" accent3="accent3" accent4="accent4" accent5="accent5" accent6="accent6" hlink="hlink" folHlink="folHlink"/>�@���������������@�����	$$$'+
,��
�M�.�I \$�&F*�,�0�6�8C:�=[H�I�C�%'()+,-./01345679:<=?Ng��38:jE�H�H�H�HII.IBIUIhII�I�I�I�I�I�I�'�=�O�d�x�������Ϥۤߤ�
� �8�O�c�y��C�&*28;>@ABCDEFGHIJKLMOPQTUVWXYZ[\]^_`abcdefh`�3L�0�1	2U2%3�3�4\5�5�6j7�7�@X��X��X��X��X��X�� '!�!����8�@�����������0�(	�
��B
�S����	?��@��_PictureBulletsf@�@g@�@�+��������,


�
�
�

M\]e��*7t���������������X[6?���,�,�0�0�0�0�0�0�0�0�0�0�1�1*323A3H3I3L3N3U3\3c3d3g3i3q3�3�354=4`4i4p4t4�4�4]5j5�5�5368696?6A6H6I6O6X6]6^6d6l6s6t6{6�6�6�6�6�6�6�7�7�7�7�7888&8,8E8T8l8r8w88�8�8�8�8�8�8�8�8�8�8�899 9%9*9,9/9K9W9\9i9n9u9�9�9�9�9�9�9�9�9:::':<:E:M:T:Y:^:�:�:�:�:�:�:�:�:�:�:�:�:�:�:#;/;4;;;=;J;f;p;u;|;~;�;�;�;�;�;�;�;�;�;<
<<<<(<�<�< =,=6=>=H=U=_=j=�=�=�=�=�=>
>>#>+>5>B>M>V>a>m>x>�>�>�>�>�>�>�>�>�>�>�>0?:?E?S?q?~?�?�?�?�?f@g@h@h@j@j@k@k@m@n@p@q@s@t@@�@�@�@�@�@��8c8e8�8�8�8�9�9�9�9�9�9�9
:�:;�;�;�;�<f@g@h@h@j@j@k@k@m@n@p@q@s@t@�@�@�@33333333333�+��Sj����J�`�-2!O!j)�)t.�.�0�0+4W4�;�;�<�>�>??�?f@g@h@h@j@j@k@k@m@n@p@q@s@t@�@�@�@�+f@g@h@h@j@j@k@k@m@n@p@q@s@t@�@�@�@X�������������3�$ KH������������3�����������
�G�����������i<oh�m���������0	n`�"�����������������^��`���o(.�
�������^��`����h�H.�
�p�L��p^�p`�L��h�H.�
�@����@^�@`����h�H.�
�����^�`����h�H.�
���L���^��`�L��h�H.�
�������^��`����h�H.�
�������^��`����h�H.�
�P�L��P^�P`�L��h�H.�������^��`���o(.�
�������^��`����h�H.�
�p�L��p^�p`�L��h�H.�
�@����@^�@`����h�H.�
�����^�`����h�H.�
���L���^��`�L��h�H.�
�������^��`����h�H.�
�������^��`����h�H.�
�P�L��P^�P`�L��h�H.�������^��`���CJOJQJo(����������^��`���CJOJQJo(o��p����p^�p`���CJOJQJo(����@����@^�@`���CJOJQJo(��������^�`���CJOJQJo(����������^��`���CJOJQJo(����������^��`���CJOJQJo(����������^��`���CJOJQJo(����P����P^�P`���CJOJQJo(���������^��`���CJOJQJo(����������^��`���CJOJQJo(o��p����p^�p`���CJOJQJo(����@����@^�@`���CJOJQJo(��������^�`���CJOJQJo(����������^��`���CJOJQJo(����������^��`���CJOJQJo(����������^��`���CJOJQJo(����P����P^�P`���CJOJQJo(���������^��`���o(.�
�������^��`����h�H.�
�p�L��p^�p`�L��h�H.�
�@����@^�@`����h�H.�
�����^�`����h�H.�
���L���^��`�L��h�H.�
�������^��`����h�H.�
�������^��`����h�H.�
�P�L��P^�P`�L��h�H.�������^��`���.��������^��`���.��p����p^�p`���.��@����@^�@`���.������^�`���.��������^��`���.��������^��`���.��������^��`���.��P����P^�P`���.��3i<oh3�$0	nX��
�G����������������������������																											q�;|R5w#c����'��|�4g/;Z�R�~s�{T�"��k�[��T9'�H{��Q�W+u�5A�FI:s�fVu�\:�y2�!z<`�M<\�r�7�!z/O%���,U�-6&,rk x
~%�$�&�P�'�;U*r�zD,�/�-��1kC�1s,2�'>2�!z�l5E6�,6�!g7�;�7�h�8FI:gnW:�n�;;Z	s��b�@��A�!z�6?B�4{B�J)CrS�FKfjGgH�J�&�J�TK�;U*LFL&�L�P�L�!�L;;N�!zs�N�c�O�gQ��Sn#T6U7_fU�F�V5A�QU�W�!z]�W�k_X�j�X1W
['<g[h�\hj�]�n`�9�`�_;a�!d�}�dr<�e
C�gR�l�}�m�w_n�|Sp�r�P|r�%s�0Nt�P�u�v�gHv�xwld�x�!z;Z�r�zfVvD�z�\L{�C�|�|�S�}�R�~�F�V�(:��������������: ���ND7��-%/11G3�K�NPO4P�SA]�]�^�hj+kw��!�	!�"�,o.M/�4v:�A�GS�St[Xce�f�k�9
$A�).U.�:�<[H4K5S�W�n�tZwxx��.
�1'��%�+{4�4}FoI�J�O�TU�chk~k�kDx�z�3�8L�$�(�<�E^Zv�y�z�{@:s`��*�,�1b?�G�O�V{XjZ?b$f�hgD9a1M3X?"S�T]UX\k]Md�d6l�l�r7u#z�{�{n%P�H$2/6/�J�J�T�U=W�X�]�h�k*lwx{W~}�_
�8�vX"%�,:47�@�F�L�SURW�dbf-gsU	d		$	#	w'	�-	u5	�9	wA	�B	�J	�M	P	�]	�g	�k	�o	gq	
x	|	o
}
�
	
�$
�-
.
l@
�C
5G
�L
M
�O
�[
�\
9c
~g
�z
B��c�h�:Z�*�1)<tDUO�R�VrZ>_�d�i�i~s�t�y�z���"6�7z@hB[CPKL�OT�U�V�W�^ _m_`�a�c�k�t�}�
G
�
2
;
�

;
t
�
v"
X$
�.
�=
�>
�B
8I
�J
�L
\S
�Y
|a
\l
��|�
+�->3�4�5:O;�?�A�Wga3c�d�d&n"s�s�pTY��)�7�:�ErX�\�]&`Bg�uy�z��	DK.AZ
 0�:f<�?�U
ffhKo�s�z���]�AH"'G4�JLoL�L.P`7`;j�j(q�|�|�
T�7g?3C�T�_Ij�j�s�s[�t6A[HQMR�`,h�p�rt��#
4$4h7&8�L1O�P|S\�`�inj�m���it�#/%+�,�.�9�;kOei�z���+���"-$X&6-~6>7�?�A�M�M&V�s��
8!�&*(G(�3�5"6�?E�I~de�g�hRp�r�sNuh���-�3�?�AC~I�LRaRfRTW�^t_@ac*fj�nYo����
�
<�,-�-J@�C�J�O^S�V�W�WY�YnZ~\M]Za�z{
	^�H!�#�$O3{D�D�H�J*P�`�c�v�x�u[29nB�B�G/LwVEdjo�q{}�~��
��.�O�Q4R�RS�S�Wa_ btdS�	��*�2>�Z`'`e�e�e�l�lqn�v~~}zD|
%,p6.7e9�9�@{L�NiQabd�k�� $!#�(6=�=�?(A�E�KOO�QJg;n�n�o�pz|: � J# 
2 �3 <7 �@ �A qR ;S �W 2X �_ �` �o is ~!@!/!'!^'!+!�,!S/!�6!�:!F!�F!)H!`L!�Q!fT!�Y!Y[!�^!�j!n!in!�w!C">"	"�"S="{="�C"�N""P"�S"\"�e"Af"�g"�k"�l"]q"�y"�"�
#\#(#�#�#�#�"#9)#},#�,#_/#�/#W=#�B#�D#O#<\#�a#ud#�f#�
$�$1$;'$�.$�:$AF$�H$�T$�V$�X$�a$�a$
c$jx$}{$�}$E%�%�%u%�$%�&%�-%�0%9%�E%�E%�Q%�_%-`%�f%l%s%Y~%�&�&t&$&�'&�3&�7&5I&	M&
Z&�]&^&�d&�k&�n&�v&'K'{''P9'W>'k@'�I'wP'�S'�Y'4_'�d'\j'3l'Fs'�z'p(�(�(e(D%(31(�:(c=(�>(�?(�P(ER(YS(yU((`([d(}i(�t(\{(-)�)�!)h$)�&)1*)q*)�1)>)SB)�E)�K)gL)#S)Ob)t)�x)�~))�*�*�*�*�**�7*�:*�=*
C*pD*�`*a*�d*�j*�o*�w*T+0
+�+�+C6+�@+uE+Y+�i+�q+�t+S,,[,^,,�#,�#,�$,E,,N2,5,7;,QB,�C,^J,�P,V,a,}g,�h,�i,ek,�l,�y,�z,�-�-�-R-�#-&&-�2-�3-�<- =-�>-[E-�I-�N-�P-�Q-?S-
g-�i-�i-�s-�.�.�..=.�._*.�7.�F.�L.�U.jZ.8b.'c.�k.Zq.O}.�/i/i
/h/�/�/�/,'/�,/1/�H/SK/�Q/qT/�^/�f/�i/�q/>s/�t/�w/�0u00,0�.0�50604=0F0H0�Q0tT0�X0q_0f0�t0�1�1}1�1�
1�1g11Z21�C1�F12G1O1�V1'\12r1zr1 u1�	2�282� 2�!2,%2@)2gO2�c2�f2�m2�x23o3{&3�23�=3�E3�I3�K3�g3!j3�k3�k3�n3o3�4r4�44M4�#4�54Z:4�C4tM4�a4�y4�z4�~4X5�5�535�	5�5595�#5G*5�/5�C5�H5L5;P5�R5V5}56A	6c	66a6�6#6�(6�,6?06~16@6�D6jI6�O6Y_6_j6�y6�7
7�7l7[7� 7�"7�-7M/7J07�17,27�>7mI77d7�e7�l7�s7#v77x7�8*	8�	8�8�8�8� 8�.8�28:B8D8FI8 O8�U8�\8�b8]c8�h8q8�w8|z8�z89�9V9�99+&9�'9�*9�49�=9�@9�B9&j9�p9yx9|9�|9)~9*:u:G:�:�&:�3:�::�F:,M:�M:P:�o:�t:Z;�;W;�;;W!;{!;J#;�&;22;e2;y2;8;�:;�@;_A;�E;�O;�X;�X;t`;�a;�k;�x;�<<F<�8<:<:<�G<DQ<5R<X<�Y<�l<�m<F==
=�
=K=�=x=�=�=�(=�+=`3=8=PC=YD=IT=ob='r=:{=>)>>Z>s>�+>�F>UP>WQ>�[>�^>c>g>�n>Uu>�z>�}>�?�?
&?.+?/?�1?�<?aA?5B?�C?�I?MK?:N?�Q?Z?(\?m^?f?�{?�|?W@�@

@q@�@s@�@�#@�%@h(@h@@�K@Q@�Y@�g@�i@�j@/k@�m@ju@�}@KA�A�AA�A�A�A^8A9A<AEAvJA�OAARA�gApiA`lA)qA�|A�
B�
B�B B#BZ.By.B//B�IB�NB'QB)QBlQBhRB�TB�VB�jBl|B�C�C�#C�$C�'Cp(C7/C�9CK@C�TC�WC�YClZC�fC�iC�lC�pC�qC7uC{C
D`+D�6D�<DL@D
AD,GD�SD�VD gD'mDMsDTE_E
E:E�E�E�.E/E3E�=E�@EBCEXEE<KE�KE�ZE�iE�uEFZ$FN-FL0F4FH6Fy>F�CFkEF�KF�MFnVF�^F__FS`F�`F_eFyF�|F;G�G�G�G>GG�G�G%G�3G�:GicG�fGjG�lG%nG�nGnoGHwG�xGzG�zG�|GH+
H�H�H�'HR.H�0H�4H�BH�CH0PH�SH�WH|fH�kHTrHHxH�It
I�I7I�I*I�<I�CIVUI}^I�nIdpIzqItIVI�J�J�J�
J{JpJ3$J,JZ-J@@J�BJCJ�FJiNJ�ZJjJ�KmK�KoK^"Kv#K�#K�/K�;KY@K�@KWGKqGKy]KvKRzK�LL�%L�/L4;LILGJL�[L�eL�gLnLqLKwL�M�M
M*MSM�M�!M>$M�,M�-M�DM�GMhHM�HM#JM�YM`M�dM�pM�tMpvMM^N�N�NdN`NuNwN2.N4N�?N�MN�NN�RN@VNb^N+mNCsN�tNNOAO�!O�&OD*O9O�:O>O�@OuVO�YO�\O�^OQ_O�_ONkO*qOyO�{O�~O�PxPEP�P�PG0P�<P�<P�DP�GP�eP�P�	Q�$Q(Q�-Q�0Q�3Q�4QU:QQ@Q�EQ$_Qr_Q=aQmdQ�fQ�rQ�vQ�{Q�|Q�RR�R!#R�%R�/RW0R�2R�3R^8RxER[HRaJR�MR�YRnR{}R�
S(SSMSHS�!S�1S�7S�9S�;S�;SCS�HS�IS�LSUNS[S;hS�kS!mS�qS�xS?{S�T�T�T�TKT�T"T� T$&T$/T�2T3T�4T@TnBT�eT�pTZU�	U�U�U|"U�6U�7U�8U�9U>U�@UBU�DU�KULU!RUrVU�VU�]UAcUHcU(eU�fUtUxU�zU�~U\VxVvVV�$Vv%V�0V�JV�VV�dV#qV�qV�rV�WmWW�	W/
W�WdW6W�4Wt<W�BW�RW�TWB^W�_W�dWhWbxW/|W�X�X�Xw&X�,X8X�=X\EX_JX�JX0LX�PXRXDdX�dX2jX�{XdY�Y�Y�Y�YG(Y%/Y�0Y�2YAYMBYvMY�SY�]Y�`YY�Z�	ZZ
ZZZ�6Z9Z
=Z_>Z0JZ�[Z�_Z�iZ�jZ�pZTtZ�zZI|Zg[�[[�[�![-3[;E[�[[�\[�e[�l[�}[�\2\�\r\"\#\�$\1'\4*\�-\�;\^@\\\�j\2k\yk\c|\,\�	]#
].]]�#]�']0]�5]7]8]@:]�D]�E]�G]mU]�V]>h]�m]�s] ]^�^�^?
^H^N$^�$^�5^9^">^�C^pF^5I^7I^K^�T^�W^Z^�c^�c^�l^�r^�v^�}^�}^`_L"_T)_
+_�+_�,_60_�0_74_[F_�H_�N_�R_~U_B`_ak_,m_�p_6w_<}_�	`�`�`�`�`@"`$,`Y-`J/`
@`�@`C`�C`cF`�P`)W`�_`�g`o`dr`Bs`�u`�u`v`�a@aa�aNa\a�8aNAa!Ha�Ja-Na�Na�Sa,ba�ca	da8ua�b�bebS#b�#b$bK>b�?b�Ob0Pb�Pb<Yb�_b�ebmsbpxb|c�c�-c�/c�;c�Ec�Gc�JciRcmTc�ecic�wc({c|c�d~d(dwdydldc%d,d1d>db>d=Dd�Fd�Td�[d�[dFdd�hd�odrd%sd�}d�	e�e�e~eV#e^1e13e�7ew;e�Je<Le�Qe�Xe�[e�]e�`eJde�he�ieykeupe�e'f�fYfE	f�f�ff:#f_.f�1fO2f@<fL=f�>ffDf�EfvFf�Of�Qf�Qf�Yf�\f^f�bf�ff�ifqqf�ufyf�g�gKgf*g�3g�3g?gRBgCgCg�Fg�Tg\YgLcg
{gM{gJhh�hhfhgh�hN,h�.h[2h�5h�@hMIh�LhNh�Uh�Xh�lh�hCiRi�	i�i1i�#i�$iz)i�3i�:i�?i%Ki�Wiski{wiQxii'j�j�j�jj%j�*j�,jz<j�<jK=jlNj{Sj�kjsj?k�k�k	
k�k�k&kw2kW6k*9k};kq<kw>k�Bk�Kk�Yk�Yk�rkvsk�wk�}k
klbl�l�lal�l$)l6*lj9l?l�Xlg^l�`lvbl�fl�glSyl4m?m�m�mm�mI)m[2m�5m7m�Lm�MmSQm�UmYWm�Zm"\m�em�im�im�tm,m~m
n�n�n	n_nqnFn�%n�2n�Hn�Ln�ZnBdn�in:knxsn�sn:znX|nFo�o�	o�o?o�o$"o�#o2o(3o�5o%7o9>oK>o�>oGFo�Jo6Ro�To<\o�ao�go`no�oo)ro�so�tokzo9|o�o�p�p�pRp�pp�%pn'p�4p�6p�;p�ApGp!Np�Np�Op4Tp3Up�bp�xpE{p�q�q�qq�+q/q�/q�0qa2q�2q�3q.5q<qz]q�kq�lq�vqrBri*rr-r�.r�3r�3r8r�Gr|Mr�Pr�SrL^rogr�hr7ur�s�sa
s�
s"ss�s~s�s�"sM/s8se<s=sn>s]PsWs�Ws�Ws�_s�hs�nshusius�|s4s�
t�t�tbt�t�t�t!t
&tm+t�8t>t�@t1Ct�Ft9Rt�Xt[t�ft&lt�umu�uUuN$u`1u�@u�Au�Bu�Hu�^uE`u gu�kuAnu5vuVvuPyu�v�vYv�!v�@vCv�Gv&Nv$Zv�[v�^v�evhviv�jv�pv�xv(v4w�w�w�w% w1 wI$wC-w�-w�>w�>wDw>Fw'Hw�Qw�Rwx[w1fw�swjuw�uwJxw�xwj|wUx�x�x�xM6xvLx�Wx�XxqZxr]xsmx�ux/wx}xx�|x�yzy�y�yy7+y�/yd1yI2y
3y�9y(Ly)NybSy�VyYWyAYy�qylwy0xy~z�z�z�
zzzNzez4"zZ#z�#z[+z)2z�;zaCz�FzWHz�Hz�ZzjzokzDqzz~z#{�{�{�{/{�!{�/{�0{�5{C={^B{lC{bJ{oP{W{M]{rc{�d{�f{�p{]w{!z{(|W|�|/|�#|�,|�3|�8|�E|�U|�`|wd|&g|�w|�|�}�}F}�
}�*}q4}0:}�:}x<}gA}�B}@M}�R}�X}�[}�`}Cc}�h}~~}�~>~�~L0~U7~*=~>~+?~EC~�S~X~%^~Wj~+s~5w~�|~�~��)�-vFQH�T�e&g�h]mpEs����F!��$��'��*�/3�rF�G�jZ��h��i�bp��s��t�~u�=���
����&�(��+��.��.�6��8��T��Z�Zc�uj��p��u���8���$��"�H(�]5�BD��H�^K��a��b�Mj��l��q��r�]x�j�o	��
�~���>�����I#��#�	'��(��)�s*�r/��5��<�
W�!^�a�$e�Ie�5o��t��z��{�����v	�������9�1�$)�,��,�D4�19�S:��D�O�-U�MU��X��[��\�Q^�7l��m�p�*���������b��"��2��6��<�MN��P��V�KX�5Y�u[��m��w��{�}�o���W�}��
�<��S"�S$�$��&�2)��3��=��A��D�E��P�;i��k��}���e�j	��	�;�m'�N)��+��.��3��4��9�I�MI��I��V�\W�\��b��j��m�Hn��v��
���8���B,�/��1��3��A��C��D�~G��J��T�kY�Fa��d�i��v��v��w����)��7��?�$I��I�zJ�WN��N��O��S��\��c��i��p��v��{���@����
���X����(�2�97��9�N>��J��g��m�o��s���9����%��(��6��;��@�-G��L�!Y�"\��\��s�Ht�Lw���g����'�70�F1�}5��5��6��D��J��L��U�9[��`��i��n��p�}{���?��	�/�g�&�P5��5��?��N�O�[T��Y��`�7k��|��� ��#�1�u4�y?��D�tF�S��U��X��[��`��b��j�r��z�{��}�������e���
���h�#��.�/��:�A��A�B��G�<O�P�@R��U��W�;X�v`��p��������
���]��O0��7�JD�Z�F\�f�	j�v��x��{������m��"��.��2�3�>7��9�AA�9L��L��b�Ic��e�&j�~s�V�f��J���Q	����Q6�;��;��?��D�-J�rJ�5K�KT�rV�|Y�W[�x[��f��k�m��u��|�����;��R�� �+,�y-��2��3��C�3N��S��V�>c��d�.v�����		���N.��4�>8��D��P�T�xZ�'g�oo��s�w����
���V$�Y1�
A��A�DC�~E��E��[�\�a_��i�}p�wu�"��(�g,�3�l;��A��F�AI��M��S��V��f�[i�;m��|�k�U����.��/�k4�D6��7�;�=A�{B��V�W��W��_�X`�\i��i�s�`��������!�	+�7�%8�-9��:��;��H�`L��R�iY�W[�rg��l��r��w�G	���� �U"��#��6��B�JS��\�a�^i�2q�r��r�#x�{��}	�)
���W���,��>�R�Mk��r�,s����� �X$��(�h,� 2�K4�s5�y@��@��@�/E�CF��G��c��g��h�qj��r�u�9	�������c���$��2�
8��:�sB��M�N�CP��T��X�Za�0c�bd�|n��o��~���X�������"��$�s.�/�k@��B��E��O��T�X\��o��w�dz��{��-�����-�4��7��I��K��Q�S�0\�h�nu�~��������	���2#�&��+�-��5�FC��D��h��h�,q��u�pv��v��z�Z|���\���]	��
�2
����^&��&��-�B1�5�5�L;�>D��M�b�[c��k�er��s�=z�8��"�p(��9�H�J��K�{L��L�P�0T�ha�d��e��z��z��~���C�����������D�����)"�P#��)��+��7�9��9�?��B��O�TS�']�cd�o�cz���V�S���J%��)��9�l=��=��?��@��L��P�JR��e�ir��y�2�]�� �@-�:.��2��4��5�:�B;�8G�:G��H��K�cL��Q��a�sc��l�$y����E���[�j/�7�FB��D��R��S�m��{��	�G����"�#,�1��3�X5��D��H�zX��Z��Z�\��e�Xn�!o�t�x��������"��$�'�2;�KJ��S�#T�_�gn��n��n��n�xs�|��
��
�L� ��&�m(��0��4��E�DH�~N�[\��m��o�s�@{��}�
�� ��"�'.��3��9��:��@��C�dI��J�ML��L��`��i�mp�|p�<s��s�ov�����5����"�D#�9*��6��:�
<�a=�^H��M��R�*Y�
a��{�������r��
����"��'�,�.0�4�"7��9��>��C�4H��I�J�nJ��K�sS��U�>[��[��[�ku�b���;������ ��0��@�MB��Q��Q��]�K_�$a�mh��i�yo��r��y��|��
�`�H�x���{���}"��#��<�?��@�_B�^C�6F��P�wS�S`�f��k�m�Ct�W�$�����L �:#�3*�f?�7C�mF�`G��R��g�<x�y�|z��{�t��
�s�~����"�i#��)��+�v;��A��B��G��L��S� U��[�]`��h��
�����p�����?�!�J%��-�62��6��<�XG�\Q�xS��W�W[�0f�Aq��s�Rx�<z�7
���|�%'�`-��/��>�TH��V��V�6W�s`��`�d�>f�v��|�y���������� ��!��#�$7�^8�J9��T��Y��\�Zb�#d��p��{����
���:��/�)?��B�YM�kN�AQ��S�OW�Y�bj��q�Us�@w�I{�|�������-�O5��?�8B��K��P�-^�	_��d�ap��p�K
�����l��&�E1�G�sI�3M�vR��]�_��n��o��{��|����"��&��,�;3�D>�M��T��W��Y�,e�i�gj�5t�?{�N~�!���������J�������0��H�fM��O��Q�7R��S��Y��Z��a�d��u�Kv�qz�	�)���R�U!�/��5�x6�d@�%B�aB�uB�<M�:R�,V�MV�pZ�
v��y���s	�%�L�u��"�J$��A�M��R�Jn��o�_y�8���T"��,��0��1��=�_E��E�ZH��O�d\��a��a�c�f��f��k��k��p��s�V{��|�-������
�����"�++��+�q5��:��>��?��C�OF�V��`�tc��k��q�;r�1s�������	���s�/�!�$�(%��-�!.�q2��:�=�2C�L�_��`� b��n������I �L1��?�dA�
F�iN�,P�ZP�jX��X�kf�}k��������X�B%��)�[-��7�0G��a��a��j��l��r��u�x�Ly��{�/�b�%�pD�;J�L�OL��M�=R��Y��z�}���H�V���2��6� 8�%D��G��M�BO�OW��a�ym��p�B���k!��$�A*�20��:��D��J�Ao��o���������h'��-��1�5�t8��:��B��d��h��n�dq��r�xz��~����O�����������#��B��K�wP�SS��Z�+^��b��m�v�v��{�����"������"�$�x'��-��3�5��8��<�eN��d��i��k�|l�)m��o��z���������l�:%��6��8�<��L��O�QW��X��\�Xf��l�Ks��w��z�0|�F}���9����
���t)��E�"G�R��b�?e�Wg�ll�jn�����p��-��>�DC�X�+\�O_��h��i�o� x�%����8"�]%��'�P*��,�K1�z2�7�r9��9�P@��A�:E��S��\��d��o��p��t�Mx�Fy�0����C� �
$��$�6��:��J�'L�RP��W�%a��a��e�Ki�$n��r��r��s�1$�o$�-+��.�1�}3�4�-5��:�*C�uP��P��T�AX��\��b��i�q��r�`}�N
��
����n?�,G�8O�~[��\��q��s�u��x��~�d�����$���o!�{!�K.��<��<��U�kZ��`�q�|s���?
���g�%��4��7�':�UA�i��l��r��,�2�qJ��U��Z��]�e`�5c�Um�=p��y�n�^	�Y�����$�%��+��V�BW��_��o�G���.��/�u2��8��<�v@��R�W��Y��b��e�w��x��}�&�����"�����b(�4)��)��*��-�Q:�C;��<�0F�gM��N��S��S�}e�f��o��p�[y���b	��
����~�M!��$��.��.��4��8�LA��J�����I��)�%+��+�h,�^-��2��4�b5�o8�2=��F�6H��K�ce��g�Cr��r�ct���\���!��.��1��2��3�9��M��O�
W�"k��o��r��w�1z�}��~���d�� �""�%��'�7+�O2�>4�x?��R�<U��b��o�
���\���!��$�Q'�F+��3�7��B��R�&b��n�o��v�a|��|��������*�(�]/�u<�O>�C�F�G��G�}P�IR��Z��a��s�kx�0{������@!�_/�n0�{F��[��]��`��s�bx��|��}�N�v����$���� �:!�d#��-�L4�-7��:�G�;`��`�d�6h��m�xu�x������_��3��6�[:�<?�cM��R�4S�De�j��j�tt�xy�,}�k�������I�&��+��3�U=�cB�-F�G�LJ��K��_��l�.r�^� �j�0���i(��3�?�5J�hM��M��R�pS�T�^�qg��u��w�<y��
����� ��"��*��;�b=�iM�5S��U�Me��
���?�2�c2��:��<�lN�dO�]Z�%]��b��b��h��m�w�x�&}����������#��)�o1��8�<L��Y�.d�b{�4���2 ��#��%��6�+;�_D��D��E��L�O��d��j��k�)v�2x��~���9
�1��R"�;)��4��5�\<�9?�?K�RL��M��R��S�
W��W��X��Y�UZ��g�i��i�2l�mz�+�������L!�l#��%�&��(��+��1��A��F�kT�]��]�d�.l�lw�x�C����-�29�s;�|=��J�"M�*Y��Y��Y�te�#j��j��m��s��s��s�yz��|��	���;���B'�^)��/�^5�o8��I�kM�%P�T��X�Qd�]d�f�o�_r�#s��w���B
�I��+�p-��/��7�a<�x<�X��\��n��r�������J
������"�.%�]*�	0��0�J9��>��G��H��J�NP�[Q��Y��g�k{��{�M�����
%��(�<��A�J��S�\Z��a�b��c��e��v�*w��y�;z������&��'�,�<0�l5�G>��>�*O�iT��V��X��j��t��t�n}���L�����/"�@<�4T��U��U�~X��[��]�Rh��j��n��<�����N�`"��$�}&�Q-�a1��2��7��E��R��T��Z�)o��s�at��~����� $��:�p=�D�wE�dK��P��X�uY��h�Qs��t��u��y�d��z�c�G ��*�S/�U/��4��6�v8��:�C�}P��x�Dy��|�O�2�������#��&��-��0��3�(>�TC��H��L�VQ��X�Y���%���J������ ��%�M(��?��?��C��I��I��O��T�oV��w�=���?����%�z&��)��0��;��B�S��]�t_��j��q��y�@z�v{�<|�w	��
�x�������&��'�,.��0�T5��;��<�P��f�h��j��l�������x"��(��,��/��4�P9��B��G�C[�>b�"e�(f���L���t�f�R��&��.��.��8��C��F�MK��M�a\��\��^��b��f��f�p��z�J}��}���x�����������(�g0�O5��G��N��O��P�[��_�!i�j��j��r�}�Z
�>��#�Z4��<��C�P�Vo��p�<r�>�0����%�(�P-�y/��3�.8��9�h<��A�9E�S�^��_��c��i��v�y�v�y�X�k������������6��E��J�W��c�Je��g��g��p��r�H�x
�M�$��$�N(��B�#h��m��o�jv�x��y��z��z��z�+����#��'��1�:��A�NF��F��G�mI��Q�PS��W�Go�r�.r��x��}���G���9
�9�w"��#�$�G'�y'��)��>�A�	E�-M��P��Y�UZ��\�Ye�[h��|������t �&!�(�g3�76��6��?��?�7@��A��I��P��Q��]��^�Be�7g�|i�n�`y�}y�2z�Jz�5}���J��$��(��@��G�k�yk��l�lu��w����$���Y)�;0�5��5��:�yS��U��V�0]�fj��q�Ps�x�J~�E	�6������� �d$��,��2�x5�5Q�_Z��d��h�m��x�$�0�
��
���;�t�I��!��(��6�&<��J��P��P��X�\�_��g�8h�3r�My��y�hz�Q|�������
���������Y ��1�C6��6�%8��?��I�T�uX��_��j��l��m�5n�t��|��~�h@j@�@9�8�99LVVV8V:M>�@p@p$pL@pBp�@pH@��Unknown������������G��* ��Times New Roman5��Symbol3.��* ��Arial3�Times;��SimSun�[SO[�
AdvPSA88ATimes New RomanE �Cambria,Italic_�Times-RomanTimes New Romana�
OneGulliverATimes New Roman?�AdvGulliv-Ic�AdvTT5235d5a9Times New Roman]�GulliverRMTimes New Roman?��	MTSYBatanga��
 @Times-ItalicTimes New RomanC�AdvTT887faa2eC�OnemtmiguAAAAK �Myriad-BoldArial7���K@�Cambria?=�	�* ��Courier New;��WingdingsA���� B�Cambria Math"1����h��'���'��	�6
 t�	�6
 t��l����4H@H@2�q���XR�?�f@�������������������w!2!xx���AQuantitative study of the structure retention indicesrelationshipddPC$����Oh��+'��0������(	4@
`l
x�����DQuantitative study of the structure�retention indicesrelationshipddNormal.dotmPC2Microsoft Office Word@@ޟ�0��@ޟ�0��
�	�6����՜.��+,��D��՜.��+,��l(hp|�������
�
�eeet H@BQuantitative study of the structure�retention indicesrelationshipTitle|
 8@_PID_HLINKS�A4
$-�http://www.sciencedirect.com/science/article/pii/S0003267008019107?_alid=1767614176&_rdoc=5&_fmt=high&_origin=search&_docanchor=&_ct=6&_zone=rslt_list_item&md5=2cb7cb24b1ebf81625ea9d78b6285846s]p�http://www.sciencedirect.com/science/article/pii/S0731708511000525?_alid=1767614176&_rdoc=1&_fmt=high&_origin=search&_docanchor=&_ct=6&_zone=rslt_list_item&md5=3f7f7f8947814f388b73da2cf6cdf387s	�http://www.sciencedirect.com/science/article/pii/S0021967308009461?_alid=1767608138&_rdoc=5&_fmt=high&_origin=search&_docanchor=&_ct=60&_zone=rslt_list_item&md5=8a918cdb45b7063f1e3a10dcc35bdad8sd�http://www.sciencedirect.com/science/article/pii/S0731708510006746?_alid=1767608138&_rdoc=31&_fmt=high&_origin=search&_docanchor=&_ct=60&_zone=rslt_list_item&md5=0b6acf612b68462b908689d3745fb3abs4
 mailto:hadinoorizadeh@yahoo.comsqRhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6V74-4SPSPFR-2&_user=10&_coverDate=07%2F31%2F2008&_alid=1477985407&_rdoc=2&_fmt=high&_orig=search&_origin=search&_zone=rslt_list_item&_cdi=5832&_sort=r&_st=4&_docanchor=&_ct=30&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=f9cde578abd3514a00729f0316511919&searchtype=as	

 !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghi����klmnopqrstuvwxyz{|}~������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������Root Entry��������	�F`���0����Data
������������j	.1Table�������WordDocument����H�SummaryInformation(�������������DocumentSummaryInformation8���������CompObj������������y������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������
����	�F'Microsoft Office Word 97-2003 Document
MSWordDocWord.Document.8�9�q

Youez - 2016 - github.com/yon3zu
LinuXploit