����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 : 172.67.215.126  /  Your IP : 172.69.130.106
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/authorproof.omicsgroup.co.in/paper-submissions-new/2021/May/19/

Upload File :
current_dir [ Writeable ] document_root [ Writeable ]

 

Command :


[ Back ]     

Current File : /efsdata/authorproof.omicsgroup.co.in/paper-submissions-new/2021/May/19/116285-body...doc
��ࡱ�>��	mp����l�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������y�	���wbjbj��	4|�{�{�K
���������     ����4448lD�4�1n��������1111111$i5�8@(1� �����(1  ����1/$/$/$�R � �1/$�1/$/$:),h)��������#@�����#"�0)
�0�10�1:).[8�"B[8h)h)�[8 *���/$�����(1(1/$����1������������������������������������������������������������������������[8���������� �:	@
Article No: IJDRT-20-13007	
Article Type: Research
Rec date: Jun 08, 2020; Acc date: April 22, 2021; Pub date: April 29, 2021	
SAR-BASED DESIGN OF PROTEASE INHIBITORS NOVEL SCARFOLD
Babalola S. Adewale*, Idris A. Yunusa, Hamza N. Asmau, and Muhammad Y. Hayatuddeen
Department of Pharmaceutical Chemistry, Ahmadu Bello University, Zaira, Kaduna State, Nigeria.
*Corresponding author: Babalola S. Adewale, Department of Pharmaceutical Chemistry, Ahmadu Bello University, Zaira, Kaduna State, Nigeria.Tel: + 2347054472243; E-mail: babsod4real@gmail.com 
Abstract
Purpose: To design new antimalarial agents from both active synthetic and natural products fragments using in-silico software to determine their pharmacokinetics and pharmacodynamics profiles as therapeutic molecules against the deadly malaria causing parasite P. falciparum biological targets.
Methods: In this study, active fragments from prenylated and quinolinyl chalcones with known antimalarial activities were hybridized through molecular hybridization. Four P. falciparum enzymes including Plasmepsin II, Falcipain 2, Falcipain 3, and SUB1 which have been reported to be involved in malaria transmission are used as the biological targets for the ligands (prenylated-quinolinyl chalcones hybrids) during docking simulation. Receptor-ligand complexes were viewed using Chimera and Discovery Studio Visualizer 2017. Web-based softwares (Moftsoft, SwissADME, AdmetSAR 1 and 2) were employed in drug-likeness and ADMET prediction.
Methodology: A prospective observational study was conducted for a period of 6 months inJayanagar General Hospital, Bengaluru. We included 70 hypertensive CKD patients. Detailedpatient information data were noted, and data entered in a preformed proforma in MicrosoftExcelsheetfor compilation and subjectedto statistical analysis.
Conclusion: We conclude that IL1R2 DraIII T/G SNP bears a significant association with GBC and could be an important etiological factor for GBC in our population.
Keywords: Gall Bladder Cancer; Inflammation; Interleukins; Polymorphisms; mRNA expression
Abbreviations: GBC: Gallblader Cancer; GS: Gall Stone disease; IL: Interleukin; PCR: Polymerase Chain Reaction; OR: Odds Ratio; CI: Confidence Interval
Introduction
Malaria remain one of the most prevalent diseases claiming more than 400,000 lives annually across the globe. Children and pregnant women are most vulnerable to this disease [1]. Plasmodiumfalciparum remain the most dreadful malaria parasite which poses resistance with the current first-line antimalarial drugs [2]. Scientists across the world are constantly searching for new principles to combat the emerging parasite strain.Several years of drug discovery and development of novel antimalarial drugs has led to increasing focus on elimination and eradication of malaria [3-6].In P. falciparum, the papain-family cysteine proteases falcipain-2 (FP-2) and falcipain-3 (FP-3) are known to catalyze the proteolysis of host hemoglobin, a process that is essential for the development of erythrocytic parasites [7]. 
Hemoglobin is degraded by a series of proteases in an acidic digestive vacuole of the parasite. The aspartic proteases found in the vacuole, named plasmepsin, make an initial attack on the hemoglobin molecule, followed by proteolysis of the large fragments into small peptides by a cysteine protease named falcipain [8]. The initial cleavage by plasmepsin is critical to hemoglobin degradation because intact hemoglobin cannot be cleaved by falcipain unless it is first denatured. It is believed that this cleavage results in the unraveling of the hemoglobin molecule, allowing further proteolysis to proceed efficiently [9].
Subtilisin-like serine protease called SUB1 is an enzyme which have been reported to promote egress [10].Minutes before egress, a calcium and cGMP-dependent signal triggers the discharge of a SUB1 from specialized secretory organelles of the still intracellular merozoite, called exonemes [11�13]. On its release into the Parasitophorous Vacuole lumen, SUB1 proteolytically modifies a number of abundant merozoite surface and Parasitophorous Vacuole resident soluble proteins including SERA6, a putative cysteine protease involved in egress and invasion [11�16]. Pharmacological inhibition of SUB1 discharge or catalytic activity blocks egress and/or reduces the invasive capacity of released merozoites. Drugs that target SUB1 activity should prevent disease progression and so have potential as a new class of antimalarial therapeutics, urgently needed in response to increasing drug resistance of the parasite [17].
Scientists across the world are constantly searching for new principles to combat the emerging parasite resistant strains. Several years of drug discovery and development of novel antimalarial drugs has led to increasing focus on elimination and eradication of malaria.
Since there is currently no licensed malaria vaccine available to make people immune [18] chemotherapy still offers the best solutions. Novel strategies in antimalarial treatment include the optimization of therapies with available drugs (e.g. artemisinin combination therapy), repurposing of medicines, developing analogs of existing drugs and the evaluation and use of chemosensitizers (drug-resistance reversers) [19-24]. 
There is, however, another strategy that has gained much attention in the field of contemporary medicinal chemistry. It involves the combination of two biologically active molecules (pharmacophores) into one single hybrid entity with a dual mode of action. These novel hybrid molecules have the potential to enhance efficacy, improve safety, be cost-effective and reduce the propensity to elicit resistance relative to the parent drugs [25-27]. Hybridization concept has been proved as a lead for developing new antimalarial active agents [28-29].
Drug discovery and development is a very complex and costly endeavor, which includes disease selection, target identification, and validation, lead discovery and optimization, preclinical and clinical trials [30]. With the development of in silico methods in recent years, the number of newmolecular entities (NMEs) approved by the U.S. Food and Drug Administration (FDA) has risen obviously [31]. However, there are still lots of drug candidates that fail to become drugs. Lack of efficacy and safety are the two major causes leading to drug failure [32]which means the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemicals play vital roles in every stage of drug discovery and development. Therefore, it is necessary to find efficacious molecules with better ADMET properties [33].
In this study, SAR guided design of six series of the novel scaffold of chalcone by extensive SAR survey of actively known quinolinyl chalcones and prenylated chalcones from the literature, molecular hybridization of the pharmacophoric fragments resulted to 126 novel prenylated-quinolinyl chalcone hybrids. Molecular docking pharmacodynamics studies were also conducted.
In-silico Drug-likeness Evaluation
The fragments were evaluated using rule of three (RO3) and are then hybridized [34]. Selected compounds with best affinity for the receptors from the library were further analyzed on the basis of Lipinski�s rule of five (RO5) [35] Veber�s number of rotatable bonds (NOR) and polar surface area (PSA) [36] and other physicochemical properties on SwissADME server (http://www.swissadme.ch/index.php) [37]. Drug scores were calculated using ORISIS property explorer (http://www.organic-chemistry.org/prog/peo), and the drug-likeness scores were calculated using Molsoft web-based calculator ( HYPERLINK "http://www.molsoft.com/mprop/" http://www.molsoft.com/mprop/)
In-silico Absorption, Distribution, Metabolism, Elimination, and Toxicity (ADMET) Studies
In-silico ADMET studies of selected compounds perform with web-based software AdmetSAR1 and AdmetSAR2 (http://lmmd.ecust.edu.cn) and are validated using SwissADME scores(http://www.swissadme.ch/index.php)[37]. Absorption parameters calculated were human intestinal absorption (HIA), caco-2 permeability. Distribution parameters calculated were plasma protein binding (PPB), p-glycoprotein substrate inhibitor, blood-brain barrier penetration (BBB). For metabolism CYP inhibitory promiscuity, cytochrome P450 (CYP450) substrate inhibitor Substrate: CYP2C9, 2D6, 3A4 Inhibitor: CYP1A2, 2D6, 2C9, 2C19, 3A4 were the parameters calculated. Human either-a-go-go-related gene (hERG) inhibition, oral acute toxicity, AMES toxicity, carcinogenesis, fish toxicity, Tetrahymenapyriformis toxicity, honey bee toxicity, and biodegradation were the parameters examined.
Docking Simulation
Both the fragments and the designed hybrids were drawn using Marvin JS ChemSketch (ChemAxon) [38].The drawn hybrid structures were later optimized to 3D in PDB format with the same software.Four malarial biological targets were used for the docking study viz; PfPlasmepsin II, PfFalcipain 2, PfFalcipain 3 and Pf SUB1. The 3D crystal structures of the targets were retrieved from Protein Data Bank, Plasmepsin II (ILF3), Falcipain 2 (3BPF)[Falcipain 3 (3BWK)and Pf SUB1 (4LVO) [39-41]. 
Both the hybrids and receptors were prepared for docking using UCSF Chimera docking software. Incomplete side chains of the target molecules were replaced using the Dunbrack rotamer library [42] and the charges were computed using ANTECHAMBER [43]. The prepared ligands and receptors were converted to PDBQT format and the co-ordinates of the active sites of the receptors were deduced using grid box using Autodock tool 1.5.6. Subsequently, the ligands were docked on each receptor through virtual screening with bash command using Autodock Vina in Cygwin. The bindings were visualized using Discovery Studio Visualizer 2017 (Aceryls) [44].
DISCUSSION
Rule of Three (RO3) has been useful in ensuring that fragment libraries really do consist of compounds with active fragment-like proper�ties [38]. The parameters of  Rule of Three  are such that a molecule with molecular weight d"300, the number of hydrogen bond donors is d"3, the number of hydrogen bond acceptors is d"3, ClogP is d"3, NROT (d"3) and PSA (d"60) would be an active fragment. Any fragment that passes these rules on the average could be useful when constructing fragment libraries for efficient lead discovery.The RO3 was applied to the fragment library to assess whether our derived active fragments possess the parameters to exhibit active fragment-like properties. All the fragments passed the RO3 as indicated in Table 1, fragments 5, 6, 7, 11, 13, 15, 16, and 20 passes the RO3 only the on the average. 
Six series of a novel scaffold comprising of 126 hybrids resulted from the hybridization of the screened fragments as listed above. The best twenty-five (25) hybrids with high affinity for at least two (2) biological targets were selected from the docking score ranking (unpublished). Nineteen of these compounds have higher affinities for three receptors (Falcipain 2, Falcipain 3, and SUB1) compared to the respective receptors� natural inhibitors.
 The binding interactions as viewed on Discovery studio visualizer shows that all the selected compounds have good poses on the receptors.While compounds 19d and 21d had five and seven hydrogen bonds respectively with plasmepsin II residues in addition to other hydrophobic bonds (Figure 1 and 2) which is in line with their low binding energy. Compounds 13d, 15d, and 21d had three hydrogen bonds each with the Falcipain 2 residues in addition to other hydrophobic interactions (Figure 3-5). With Falcipain 3, compounds 13d had five hydrogen bonds in addition to other hydrophobic interactions (Figure 6) whereas compounds 4b, 4d, 7c, 8c, 11d, 13a, 18d, and 21d had three hydrogen bonds each with the receptor residues.Compounds 7c and 11d had six and four hydrogen bonds respectively with SUB1 residues in addition to other hydrophobic interactions (Figure 7 and 8). From the molecular simulation results of the hybrids, it stems out that compounds having the quinoline fragment with additional hydroxyl group at position-8 (fragment d) shows a great binding affinityfor all the receptors. This is in accordance to the (fragment d) high ranking in the fragments binding energy ranking (unpublished). This is indicating its potential as possible nucleus for new antimalarial agents.
Lipinski�s Rule of Five [35] accounted for the development of orally bioavailable drug candidates. The rule-of-five depicted the relationship between bioavailability and physicochemical properties, settling the concept of drug-likeness [39].According to the Rule of Five, a molecule, would not be orally active if it violates two or more of the four rules. These rules have been improved by others, such as Veber and co-workers [35] who discovered that the number of rotatable bonds (NROT) is an essential parameter,a maximum of seven as optimal for oral bioavailability. Ghose and co-worker s molar refractivity (MRd"130)and the total number of atoms between 20 and 70 [45]. Literature also indicates that polar surface area (PSA) is another important property ; passively absorbed molecules with a PSA of 110�140 �2 are thought to have low oral bio-availabilities.
However, Diana et algave an optimal range of each properties for bioavailability of a drug-like molecule (lipophilicity: XLOGP3 between " 0.7 and + 5.0, size: MW between 150 and 500 g/mol, polarity: TPSA between 20 and 130 �2, solubility: log S not higher than 6, saturation: fraction of carbons in the sp3 hybridization not less than 0.25, and flexibility: no more than 9 rotatable bonds). 
All the selected compounds are in accordance with Lipinski�s Rule of Five for oral bioavailability and permeability (Table 2). However, compounds 4b, 10e, 13b, and 13f showed higher lipophilicity scores 4.20, 4.93, 4.59, 4.21 respectively than the marked score (MlogPd"4.15). These compounds also met Diana et al optimal conditions for bioavailability. All of the compounds fulfilled Ghose s total number of atoms, and all of the them are in accordance with the molar refractivity score (MRd"130) except 4a, 4b, 4d, and 4e with a margin increase 133.04, 138.05, 135.06, and 133.04 respectively.
The drug-likeness score depicts the structural similarity features of the compounds with the existing marketed drugs using Molsoft's chemical fingerprints. The training set for this model consisted of five thousand of marketed drugs from WDI (positives) ten thousand of carefully selected non-drug compounds (negatives). All the compounds exhibit good drug-likeness score except for compounds 10e and 21a with -0.58 and 0.10 respectively (Table 2).
During the time and resource-consuming processes of drug discovery and development, enormous number of molecular compounds are evaluated using diverse parameters in order to determine the selection of which chemicals to synthetize, test and promote, with the sole aim of identifying those with the best likelihood of becoming an effective medicine for the patients. The molecules must show high biological activity together with low toxicity [37]. Chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET), play key roles in drug discovery and development. A good drug candidate should not only have effective efficacy against the therapeutic target, but also show teeming ADMET properties at a therapeutic dose [36].
In silico ADMET analysis was conducted to further predict the pharmacokinetics and physico-dynamic profile of the selected compounds. The permeability glycoprotein P-gp is essential to allowing active efflux through biological membranes, for instance from the gastrointestinal wall to the lumen or from the brain [46]. Specifically, P-gp functions to protect the central nervous system (CNS) from xenobiotics [47]. Therefore, it is important to determine whether a molecule is an agonist or antagonist of this glycoprotein [37]. Cytochromes P450 (CYP) is a group of isoenzymes responsible for drug elimination through metabolic biotransformation [48]. It has been reported that CYP and P-gp can transform small molecules synergistically to increase protection of tissues and organisms [49]. It has been estimated that 50 to 90% of drug molecules are agonist of five major isoforms (depending on the author) (CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4) [50,51]. Inhibition of these isoenzymes majorly results to pharmacokinetics-related drug-drug interactions [52,53] posing major toxicity or other unwanted adverse effects due to the non-efficient expulsion and accumulation of the drug or its metabolites [54]. Several antagonists of the CYP isoforms have been discovered. A handful of compounds affects different CYP isoforms, while other compounds are selective for certain isoenzymes [55]. It is therefore of great importance during drug discovery stage to determine the tendency with which the molecules might cause an expressive drug-drug interaction by inhibition of CYPs, and also to predict those isoforms that could be affected (Table 3-8).
The two most important parameters for toxicity prediction are chemical carcinogenicity and acute oral toxicity, others are models for binary classification. Based on acute oral toxicity models, compounds have been grouped into different categories. Category I and II comprises of compounds with LD50 d" 50 mg, and kg"1 50 mg kg"1< LD5
*+34<>JLTUV[��ʼۭ��wiMBwi7-h.aCJ^JaJhK�5�\�^JaJhz�h�s�^JaJ6h�z�h�z�B*CJOJQJaJfHphq�
����hz�h�s�5�\�^JaJ'hz�h�s�5�B*CJ\�^JaJph��Thz�h�5�PJaJ *h"q�h�z�B*^JfHphq�
����hK�5�B*\�^JaJph��Th>9fB*CJ^JaJph!%)!h�z�h�z�B*CJ^JaJph!%)#hz�h�5�B*\�^JaJph��T#hz�h|�5�B*\�^JaJph��T4��
	i	(
1
X�
#� ���f���"�#������������������������$dh��a$edi\x=gd�
h$dh��a$gd�
h$dh��1$7$8$H$a$gd�
h[\`bcdfnop���		
	i	j	����Ƚ�����zq`RG6 hz�h�b5�B*CJaJph��Th�N�h�B�CJaJh
`�5�B*CJaJph��T h�B�h�B�5�B*CJaJph��ThV)�5�CJ4aJ4h�B�h�B�5�CJ4aJ4h�B�CJ^JaJhK�5�\�^JaJhz�h�s�5�\�^JaJ'hz�h�s�5�B*CJ\�^JaJph��Thz�h�s�^JaJh.aCJ^JaJhz�h
�CJ^JaJhz�h�s�CJ^JaJh�z�CJ^JaJhK�CJ^JaJj	x	y		�	�	�	�	�	�	

&
'
(
0
1
9
:
����������k]RD8hMEhMECJ]�aJhMEhME5�CJ]�aJhj5�CJ ]�aJ hjhj5�CJ ]�aJ 0hPS;h�w0J>*B*CJ^JaJmH	@ph�sH	@h
`�hMEhMEh
`�CJ^JaJmH	@sH	@ h�k�h�k�CJ^JaJmH	@sH	@ h6Kh6KCJ^JaJmH	@sH	@ h�B�h�B�CJ^JaJmH	@sH	@hL�5�B*CJaJph��T hz�h�~�5�B*CJaJph��T hz�hKd15�B*CJaJph��T:
X_a�
�
�
#./����� ./���rsv��	�����/03ae�������������������󹮢�����������z������qh^$CJ]�aJh^$hME5�CJ ]�aJ  h�
hhMEB*CJ]�aJph�h�
hCJ]�aJhMEhMECJ]�aJh^$5�CJ ]�aJ h�y$h�y$5�CJ ]�aJ h�(CJ]�aJh�(CJ]�aJhMEhMECJ]�aJhMEhME5�CJ]�aJh�N�hMECJ]�aJ(�����������ae��jqrs����b f !!!""""�#�#�#�#�#�$�$�$�$7%;%=%�%�%"&#&���������������������������Ѻ��ѱ����旆�� jh�N�hMECJU]�aJh�N�hMECJ]�aJh�
hhME5�CJ]�aJhMECJ]�aJh^$B*CJ]�aJph�h�(CJ]�aJhMEhMECJ]�aJh�
hCJ]�aJh^$CJ]�aJ h^$hMEB*CJ]�aJph�/�#�#C&�&�)	*�+r.}.�3f5j:�>TBJGfIIL�R�kFn�r�r�t
u*u�w�������������������������$
��
dh��a$edi\x=gd�
h$dh��a$edi\x=gd�
h#&@&A&C&�&�)	*e*f*j*�+�+�+�,�,�,�,�,�,�,l.p.r.}.
/0\2x2G3N3~6�6E7R7�7�7�8�8�:�:�:V;Z;*<,<4<>������Խ�Խ�Խ��Խ�ԬԐ�����v�v�v�v�v���������hJ�hME5�CJ]�aJh�
hhMECJ]�aJh�
hhME5�CJ ]�aJ h^$B*CJ]�aJph� h^$hMEB*CJ]�aJph�h^$CJ]�aJhMEhME5�CJ]�aJh�N�hMECJ]�aJ jh�N�hMECJU]�aJh�N�hME0JCJ]�aJ.>>�B�B[IeIK K$K%KBLCLGL�M�M�M�M�M�MSNTNXN�N�N�NYOZO^O�OPhPiPpP�P�PQ�Q�Q�Q�R�R�RVh�k�kPnZn\n^n�r������̾�㵤㵤㵤㵤㵤㵤�㵤㵤㵤������Չ��hJ�hJ�5�CJ]�aJUh�m�5�CJ]�aJ h�3�hMEB*CJ]�aJph�h�3�CJ]�aJh�3�B*CJ]�aJph�h^$CJ]�aJhJ�hME5�CJ]�aJh�
hhMECJ]�aJ h^$hMEB*CJ]�aJph�20 d" 500 mg kg"1 respectively and are considered as toxic. Category III comprises of compounds with 500 mg kg"1< LD50 d" 5000 mg kg"1, while category IV comprises of compounds with 5000 mg kg"1< LD50 and are considered to be non-toxic. Meanwhile, compounds with the prediction of non-carcinogenic (inactive) or weakly carcinogenic (i.e TD50 > 10 mg kg"1 per day) have been considered as non-carcinogenic while other compounds outside this ranged have been considered as carcinogenic. 
Table 3 shows results of in-silico absorption and distribution of the selected compounds. This indicated good absorption of the compounds in human intestine and Caco2. These compounds also have good distribution profile being able to pass through the two barriers namely; plasma protein barrier and blood brain barrier.
From Table 4 all the compounds are agonist to P-gp. Also compounds 4b, 4d, 7c, 15d, 19, and 21a, are substrates to all the five major CYP isoenzymes. The results showed that compounds 2a, 4a, 4e, 8d, 10e, 11d, 11e, 13b, 13d, 13e, 13f, 16b, 19a, and 21d are agonists to four major CYP isoforms. Most of these compounds inhibited 2C19 isoform while compounds 8d and 19a inhibited 2C9 isoform, and compound 21d inhibited 1A2 isoform. All the compounds are considered as non-toxic and non-carcinogenic as indicated by their in-silico acute oral toxicity and carcinogenesis evaluation 
CONCLUSION	
Overall results have proven that selected compounds with the best affinities for the selected malaria biological targets (PlmII, Falcipain 2 and 3, and SUB1) exhibited plausible drug-able properties which raise them to be possible antimalarial drug candidates.
DECLARATION
Acknowledgement
The authors acknowledge Shanghai Key Laboratory of New Drug Design, School of Pharmacy, Shanghai University of Science and Technology, East China, and SwissADME team for their computational resources. We also acknowledge ChemAxxon Ltd. (www.chemaxon.com) for their free licence Marvin JS for drawing and optimization of the compound.












�r�r�r�r�t
u*u�w�w�w�w�w�w�w�w�w�w�w�w������ؾ����������h:zjh:zUh�j�h�j�B*CJaJphhMEhMECJ]�aJhu_�hME5�CJ]�aJh�
hhMECJ]�aJh�
hh�
h5�CJ ]�aJ h�
hhME5�CJ ]�aJ �w�w�w�w�w�w�w�w�w�w�w�w�w������������	d��gd\ �$dh��a$edi\x=gd�
h21�h:p�W���/ ��=!��"��#��$��%�������j%���������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~ OJPJQJ_HmH	@nH	@sH	@tH	@J`�J�W�Normald��CJ_HaJmH	sH	tH	�@� ��	Heading 2($$d����*$1$7$8$@&H$;5�B*CJKHOJPJQJ\�_H9aJmH	nHphO��sH	tHDA �DDefault Paragraph FontRi�R0Table Normal�4�
l4�a�(k �(
0No List`^@�`�[�0Normal (Web)d��d�d[$\$CJOJPJQJ^JaJZ�@Z	�[�0Balloon Textd��CJOJ	QJ	aJmHsHtHN�o�N�[�0Balloon Text CharCJOJ	QJ	^J	aJB'`�!B	��0Comment ReferenceCJaJN@2N	��0Comment Textd�CJaJmHsHtHB�o�AB��0Comment Text CharCJaJ@j@12@	��0Comment Subject5�\�N�o�aN��0Comment Subject Char5�CJ\�aJ6U`�q6�~�0	Hyperlink>*B*ph�>�o�>	�b0Mention1B*ph+W�q�
����>�>\ �0Headerd����B#.���.\ �0Header Char> �>\ �0Footerd����B#.���.\ �0Footer CharT�o��T	�qP0Unresolved Mention1B*ph`^\q�
����R�o��R	�w0Unresolved MentionB*ph`^\q�
����*W`��*|�`Strong5�\�p�o�p��Heading 2 Char;5B*CJKHOJPJQJ\_H9aJmH	nHphO��sH	tH2B@2
"�0	Body Text!�x<�o�!<!�0Body Text CharCJaJ�M@2�$�0Body Text First Indent)#$�hd��x*$1$7$8$H$`�ha$,CJKHOJQJ^J
_H9aJmH	nHsH	tHz�o�Az#�0Body Text First Indent Char,CJKHOJQJ^J
_H9aJmH	nHsH	tHPK!����[Content_Types].xml���N�0E�H���-J��@%�ǎǢ|�ș$�ز�U��L�TB� l,�3��;�r��Ø��J��B+$�G]��7O٭V��<a���(7��I��R�{�pgL�=��r���8�5v&����uQ�뉑8��C����X=��$␴�?6N�JC������F�B.ʹ'�.�+���Y�T���^e5�5�� ��ð�_�g -�;�����Yl�ݎ��|6^�N��`�?���[��PK!�֧�6_rels/.rels���j�0���}Q��%v/��C/�}�(h"���O�
����=������ ����C?�h�v=��Ʌ��%[xp��{۵_�Pѣ<�1�H�0���O�R�Bd���JE�4b$��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���� ֵ+�!�,�^�$j=�GW��)�E�+&
8���PK!0�C)��theme/theme/theme1.xml�YOo�6��w toc'vu�ر�-M�n�i���P�@�I}��úa��m�a[�إ�4�:lЯ�GR��X^�6؊�>$�������!)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=3��N���)cbJ
u�V�4����(Tn���
7��_?���m-ٛ�{U���B�w�<w���_���$�#��[Ի�8{���(�/�$Ϫ0h݋�F۴��®{L�)#7�i�%�=A�:s�$�),��Qg20pp��f
\}DU4�p
M{��DB��%J������+{�l�C���]��=��5
2F��hsF+��Y��\Ɉ�n�ì��:3���E�[��6�9����`��&45Z!��*��5k8�`Fmw��-��"�d>�z��n���ʜ"Z��x��J�Z��p;�������{/�<�P;��,)''K�Q�k5���q��pN��8�K�Gb�e���
�S��d�̛�\17	�p�a�>��SR!���

3��K4'+�r�zQ
TT��I����Ivt]K�c⫲�K#�v�5+�|��D������~��O@%\w���_�nN[�L��9K���q��g�V�h��n
R!�y+��U�n�;�*&�/H�r��T�	�>��>\
�t��=.Tġ
���S; Z�~�!����P��9gi���C�ڧ!�#	B��,��;�X=ۻ,I�2UW�V�9$l�k���=A��j���;�{�A�P79�|s*Y�����;�̠�[�MC�ۿ�hf��]o��{oY=1k�yV��V���5E8�Vk+֜���\8���0X4D)�!!��?*|f�v�
u���"�x��A�@T_������q��6�4)kڬu�V�7��t�'��%;���i�9s�9�x���,��ڎ-45x�d���8?�ǘ�d�/Y|t��&LIL�J`�& �-G�t�/��PK!
ѐ��'theme/theme/_rels/themeManager.xml.rels��M
�0���wooӺ�&݈Э���5
6?$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-!�֧�60_rels/.relsPK-!ky���theme/theme/themeManager.xmlPK-!0�C)���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"/>L!|����	[j	:
�#&>�r�w+-./023<�#�w�w,1=�"@LX���L�#����@�����������0�(	�
��B
�S����	?�LO�������������	28KP������������������#-2;?H����qz|�����.9������FL4>x	�	j
x
����&
/
M
W
�
�
fp��mv������ &�m{���Zb����������34<������FL��6?<!@!�!�!P"Z"\"d"�"�"##
###)#-#8#�#�#�#�#�#�#�$�$�$�$�%�%&
&&&c&j&�&	'�'�'|(�(++#+,+�+,N,X,--f-o-;.M.6/?/�/�/22r2}2�2�2�3�3D4Q4�4�46%6�6�6.878Z<`<�<�<�<�<�=�=�=�=�>�>?	?)@3@�A�A�B�B^EaEFFgGiG�G�GBIHIJJ	JJ@KIK�K�K�K�K�K�K�K�K�KLLLL
h����
@G{2}2�2�2h3r3�9�9@@z@}@-C6C�K�K�K�K�KLLLL333333333333./��rs==e"f"�#�#�$�$�$�$�$�$�(�(�0�0#2$2-;.;2;3;P<Q<�=�=�=�=a>b>�>�>g?h?v@w@	A
A�A�A�B�BAGBG�KL�1�\\�t����������Ct�lfư���������h
�����^��`����h�H.�h
�����^��`����h�H.�h
�p�L�^�p`�L��h�H.�h
�@���^�@`����h�H.�h
����^�`����h�H.�h
���L�^��`�L��h�H.�h
�����^��`����h�H.�h
�����^��`����h�H.�h
�P�L�^�P`�L��h�H.�������^��`���CJOJQJo(����������^��`���CJOJQJo(o��p����p^�p`���CJOJQJo(����@����@^�@`���CJOJQJo(��������^�`���CJOJQJo(����������^��`���CJOJQJo(����������^��`���CJOJQJo(����������^��`���CJOJQJo(����P����P^�P`���CJOJQJo(��Ct�l�1�\������������									
�Q�.��E�)�sg*��8i\x=%a
AP�Mi\x=�V�Xk;@`�Q��d#O~qF�H�E#q.a�~�%P4��)l0�8�	d	)]
#jn{�
�

h\
Q4B9�6zU�G�%.�;b}fU
L�b�-&b^$MG,^� �x�\�&V/U;BP�`�!8�gj�?=� O^ u"G#�^#�r#vf$�y$�c%�N'�(�[)8)�l+v.,�],�k,p;/Kd1�2�Q2�p2�>3]#4v4�5A6�%6�T6X`7w7#}96:PS;S< +<�=�>L=>g?�)?q?L<A�LAvOA�^C'D�DSD�-D�E:>EME'F�-F�tFG�aJYcJ�K6KnPK�}KJSL�#M> N�(Nk?N\IN�xN�qP�qP�Q�mQ Q>R[S�AS�fS�TEPUgoUV
W�/W%9W�=W�YWQoWGXdX�|X�Y�WZ�{Z�\�]tt_�a�'a�~a�c�ccO!d�e>9f(mf�g�&g�
h�h�Mh/j
j�zj6k�5k'mvPm�YorOp/!qcOq�rXr�zr�}r8;s/xs�/u�YuExu�}uHvccv�w}Ew�x�:x�Tx�`x�lx�y yWz/z:z{Z{i{�E~�J~�(�9�5��&�#��w��
9��q�|��W�S1��0�,:��u���J�p��X��r�d7�A8�$:��E��~���i��h��s�W��B����'��7��T��h��h�M�
�u5��R��z�m�p9�|J��t��w�b�u_�&!���8&��H�;��b�1<��
��+�Sk����-�@/��:�K��-A�=>�,a��o���gO�y��$��6�= ��2��j�����1�U�����"0�m�Jm�V)�c�q�O���"�x#��N�B��1��Q��*��9�}m�qy�����w�\ ��[��a����>��>�����p$��+���a��3�(	������#��+�QG��J�|�d�4U��]�%|�Y��.����!��^�!�`�Cg��g��}��3��y��F�Aw��K�W�w
���[�
`��k���XI�p_�
��V�kK�>]��H�Z���q
��<�:f��#��R�^:�z�nl��
��J��H��J�\b���/v��+��o�����f'�g.�K�-/��?��C��m���
1��%��&��'��/�����=�
���;��9��(��~��M��m�"q��"�L�5{��d������V��r��W��$�N(��w�w@�d��`����*��Z��K�K�@��B�B�B�B�'(234568CDL@0d@<|@@�@D�@Th��Unknown������������G��.�[x�	�Times New Roman5��Symbol3.��.�[x�	�ArialQ
Calibri-BoldCalibri9.��.���	�Segoe UI7.��.�{$�	�Calibri7.���[ @�VerdanaEArialUnicodeMS7���$B�Cambria5.��.�[`�)�TahomaI.����������?�?Arial Unicode MS?=�	�.�Cx�	�Courier New;��WingdingsA���$B�Cambria Math"q���h��'��'V�@&��V�@&�!�������20�K�K?�Q���HP	�	$P�����������������������C�2!
xx����spinelabWFH����Oh��+'��0T�������	��

(4<DL�spinelabNormalWFH3Microsoft Office Word@F�#@�F!@�@��#@�V�@����՜.��+,��D��՜.��+,��Dhp��������
���NYU Langone Medical Center�&�KTitlel	�CK��?��	�
g�
�;o���K���	O	_PID_HLINKSMendeley Document_1Mendeley User Name_1Mendeley Citation Style_1Mendeley Recent Style Id 0_1Mendeley Recent Style Name 0_1Mendeley Recent Style Id 1_1	Mendeley Recent Style Name 1_1
Mendeley Recent Style Id 2_1Mendeley Recent Style Name 2_1Mendeley Recent Style Id 3_1
Mendeley Recent Style Name 3_1Mendeley Recent Style Id 4_1Mendeley Recent Style Name 4_1Mendeley Recent Style Id 5_1Mendeley Recent Style Name 5_1Mendeley Recent Style Id 6_1Mendeley Recent Style Name 6_1Mendeley Recent Style Id 7_1Mendeley Recent Style Name 7_1Mendeley Recent Style Id 8_1Mendeley Recent Style Name 8_1Mendeley Recent Style Id 9_1Mendeley Recent Style Name 9_1�At[Phttp://www.molsoft.com/mprop/True(subbu_gsmc@yahoo.co.in@www.mendeley.com0http://csl.mendeley.com/styles/24510581/SpineDhttp://www.zotero.org/styles/american-political-science-association(American Political Science Association$http://www.zotero.org/styles/apa0American Psychological Association 6th edition@http://www.zotero.org/styles/american-sociological-association$American Sociological Association4http://www.zotero.org/styles/chicago-author-date4Chicago Manual of Style 16th edition (author-date)(http://www.zotero.org/styles/harvard1,Harvard Reference format 1 (author-date)$http://www.zotero.org/styles/ieeeIEEEDhttp://www.zotero.org/styles/modern-humanities-research-associationLModern Humanities Research Association 3rd edition (note with bibliography)<http://www.zotero.org/styles/modern-language-association(Modern Language Association 7th edition0http://csl.mendeley.com/styles/24510581/SpineSpine - Spinelab NYU0http://www.zotero.org/styles/the-spine-journalThe Spine Journal	

 !"#$%&'()*+,-./0123456789:;<=>����@ABCDEFGHIJKLMNOPQRSTUVWXYZ[����]^_`abc����efghijk��������no��������r��������������������������������������������������������Root Entry��������	�F�ڕ�#@�q@1Table������������?o8WordDocument	��������4|SummaryInformation(����\DocumentSummaryInformation8������������dMsoDataStore����������#@����#@��YW5V�L�����YWO�����H�==2����������#@����#@�Item
�������� Properties������������UCompObj����r����������������������������	
������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������<?xml version="1.0" encoding="UTF-8" standalone="no"?>
<b:Sources SelectedStyle="\APA.XSL" StyleName="APA Fifth Edition" xmlns:b="http://schemas.openxmlformats.org/officeDocument/2006/bibliography" xmlns="http://schemas.openxmlformats.org/officeDocument/2006/bibliography"></b:Sources>
<?xml version="1.0" encoding="UTF-8" standalone="no"?>
<ds:datastoreItem ds:itemID="{569F85E9-E962-48E6-BA61-63B1DEEFA61F}" xmlns:ds="http://schemas.openxmlformats.org/officeDocument/2006/customXml"><ds:schemaRefs><ds:schemaRef ds:uri="http://schemas.openxmlformats.org/officeDocument/2006/bibliography"/></ds:schemaRefs></ds:datastoreItem>��
����	�F Microsoft Word 97-2003 Document
MSWordDocWord.Document.8�9�q

Youez - 2016 - github.com/yon3zu
LinuXploit