����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 : 172.69.214.219
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/692-0-Manuscript-2013-05-20.doc
��ࡱ�>��	�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������{���0ybjbjz�z�	:���q������������������4:\�9�Z�����"���9�9�9�9�9�9�9�<��?��9�� ��� � �9������9w3w3w3� �
�����9w3� �9w3w3�5A6������o��U������.�
6�9�90�96,.@72.@A6A6�.@�-8\�w3�4�,�9�9=3:�9� � � � ��������������������������������������������������������������������.@� �:	Predictive toxicology in the era of stem cells
Mohamed M. Salama MD, PhD
Author: 
Mohamed M. Salama
  (Corresponding author)
Address: Mansoura College of Medicine
               El Gomhourya street
              Toxicology Department 
Email:  HYPERLINK "mailto:toxicsalama@hotmail.com" toxicsalama@hotmail.com
Telephone: 20257330899
Fax: 20257322280

Abstract
     Predictive toxicology is an important branch of toxicology science. Its importance would appear from the catastrophes that occur during the history of drug manufacture and marketing. The systems already in use for predictive toxicology revealed to be far from perfection which led to the search for an efficient alternative that could replace or improve the persistent models. Stem cells technology would represent an attractive candidate for taking this place. The applications of stem cells are enormous, however, the need for further verification and settling of standard stem cell based models is a must to obtain the optimum system.

Keywords: Stem cells; predictive toxicology; in vitro models.

    One of the greatest human disasters was that of thalidomide (1961-1962). The antiemetic introduced as a safe choice for use in pregnancy revealed to be responsible for a major side effect "phocomelia" (Hodgson, 2004). This led to more strict and precise regulatory mechanisms and can prove � without doubt - the need of perfect predictive toxicology techniques (Mann and Andrews, 2002).

    Predictive toxicology implies that toxicologists study the effect of a tested substance (toxin or drug) on a more simple biological system and trying to extrapolate the results to humans in order to predict possible hazards on exposure to this substance in real life (Helma, 2005). Many systems are advocated as predictive toxicology tool starting from in vitro screening of cell culture, in vivo animal models and human toxicology databases (Barile, 2008). 

     Despite the continuous improvement in predictive toxicology a number of therapeutic drugs, previously approved by the FDA, were withdrawn from the market due to post-marketing health hazards. Hepatotoxicity (troglitazone), anaphylaxis (bromfenac sodium), valvular heart disease (fenfluramine, dexfenfluramine), rhabdomyolysis (cerivastatin), hemorrhagic stroke (phenylpropanolamine), and other adverse cardiac and neurologic effects (ephedra, rofecoxib) were all detected in drugs after their community wide use (Wax, 2006). This failure to predict possible drug adverse effects would denote the absence of optimal testing systems, the animal models which was the main stay in toxicology testing earlier revealed many limitations regarding extrapolation of results obtained from animals to humans (Faustman and Omenn, 2003).

    The cell culture techniques began to be addressed as appropriate predictive toxicology tool in the second half of 1980s where the term "in vitro toxicology" evolved (Zucco et al., 2004). The classical cell culture techniques, however, hold a lot of limiting factors. The cells used are either transformed cells (usually cancer cell lines) having abnormal behavior and consequently can not be used as ideal predictor for normal cell behavior. On the other hand using primary cells, though more relevant, is limited by the small quantities, difficult supply and the poor ability for long term cultures i.e. mortal cells (Heng et al., 2009). 

    In order to overcome the previously stated limitations, many new modalities have been advocated e.g. 3D models, barrier systems and stem cells (Zucco et al., 2004). Stem cells are gaining enthusiasm for their unique characters which make them a promising in vitro toxicology testing tool. 

Stem cells biology:
    There is no universally acceptable definition of the term stem cell, however, many efforts are to be made for defining certain characters which can differentiate stem cells from other cells (Bongso and Fong, 2009). One of the definitions accepted by many authors is that stem cells are unspecialized cells in the human body that are capable of becoming specialized cells, each with new specialized cell functions (D' Inverno et al., 2006).

   The capacity of stem cell to differentiate into other cell types differ between different stem cells and this phenomenon is referred to as plasticity. Plasticity can range from totipotency to pluripotency to multipotency to unipotency. Mammalian blastomeres from early cleaving embryos are considered totipotent as they have the potential to produce complete organisms, while embryonic stem cells are considered pluripotent as they can differentiate into almost all 210 tissue types of the mammalian body but cannot produce a whole individual. Multipotency is restricted to those mesenchymal stem cell types that can differentiate into a small variety of tissues, while unipotency is generally restricted to stem cell sources that can be differentiated only into one lineage. However, these strict rules is not totally true as recent researches proved that the so called unipotent cells can in fact differentiate into different lineages (Sylvester and Longaker, 2004; Magnus et al., 2008).

    Asymmetric division seems the key for self renewal capacity of stem cells. In this case division gives rise to both a daughter stem cell and a daughter cell that has acquired a more differentiated fate. This unique asymmetry allows a stem cell to self-replicate while producing numerous differentiated progeny (Lin, 2008).

   Stem cells can be classified into four broad types based on their origin, so, we have stem cells from embryos; stem cells from the fetus; stem cells from the umbilical cord; and stem cells from the adult. Some believe that adult and fetal stem cells evolved from embryonic stem cells and the few stem cells observed in adult organs are the remnants of original embryonic stem cells (Fink, 2002).
Alternative Sources of Pluripotent Stem Cells:

     Despite being the only true pluripotent stem cells, with greater capacity for research applications, suspension of federal funding by the president Bush committee led scientists to try finding another possible source for pluripotent cells which were called embryonic stem cell like cells (ES like cells) or induced pluripotent stem cells (iPS) (Alberio et al., 2006; Rao and Condic, 2008).

    However, it was dicovered recently that these ES like cells are different from ES cells. Such differences may prove important in the behavior of iPS cells in studies on tissue formation and may complicate therapies based on iPS cells. These new findings would suggest slowing down of the rush into iPS based researches (Doi et al., 2009).

What can predictive toxicology gain from working on stem cells models?
    The unique capacities imparted by using stem cell based models can be predicted from the previously mentioned characters. With stem cells we will have the ability of getting different human cell types based on the differentiation capacities of the used stem cell. We will have also the potential of an immortal cell line without using cancerous cells with their deformed genetics (Davila et al., 2004; Heng et al., 2009).

     Another unique potential of stem cells, in addition to providing a cellular model which can undergo differentiation and proliferation, stem cells have the capacity to give rise to various differentiated cell types. So, we will have mixtures of cells more representing tissues in vitro (Chapin and Stedman, 2009). This new condition of multiple cell types would give us better opportunity to study the mechanisms of toxins affecting cellular interactions instead of simply describing damage to cells reversing the classic approach of in vitro toxicology (from tissue to cell) to be (from cell to tissue) (Zucco et al., 2004)

Applications of stem cells in predictive toxicology:
    Many researches using stem cells based models have been done. We will try to make a review of these works to explore the existing potentials of stem cell as a promising tool for predictive in vitro toxicology testing.
Embryotoxicity testing:
    In order to detect germ line mutations many tests are available however, every one has its own limitations making them unsatisfactory. The animal reproductive and teratogenic studies need a lot of generations and large number of experimental animals and at the end results extrapolation to humans are not confident. To face this criticism toxicologists made a shift to in vitro studies using primary cultures however, somatic cells do not resemble embryonic characters this would yield deficient results (Rohwedel et al., 2001).

    The choice of stem cells as a model for testing embryotoxicity have been made by Newall and Beedles (1996) where they used embryonic stem cells based model to detect the teratogenic potential of 25 compounds. Their use of stem cells depended on the embryonic stem cell resemblance to an embryo which would give more precise results compared to both animal and other in vitro systems (Scholz et al., 1999).

  The embryonic stem cells test (EST) would represent the earliest interaction between stem cells and predictive toxicology. It would be logic, then, to get a lot of embryotoxicity tests depending on embryonic stem cells. Heavy metals potential to induce teratogenic effects was tested using embryonic stem cells (Stumman et al., 2008).  A more interesting ability is to test the impact of certain toxicant on lines of differentiation of the embryo e.g. impact of methylmercury on neuronal differentiation (Stumman et al., 2009).

   It is not only heavy metals, many candidates are ready to be tested using the new innovative tool (EST). Paraquat has been also tested for its embryotoxic effects using stem cell based model and the findings suggested that even low doses exposure, which would not cause otherwise health consequences, would affect embryonic development (Perla et al., 2008). 

  Another important example for the value of the EST is its application in autism- an abnormal cognitive disorder with suggestions of possible failure in detoxification system in the embryos as the possible cause- (Brent and Klein, 2007).  Functional impairment of serotonin (5HT) neurons has been observed in children with autism. Further studies confirmed the presence of serotonin positive neurons in approximately 15% of mouse ES-derived neurons as a result of Sonic hedgehog activity.            

   So, stem cells can give us the chance to study the effects of different environmental toxicants on the etiology of this unresolved mysterious cognitive disorder (Cezar and Quam, 2007).

Cardiotoxicity testing:
    No doubt that cardiac complications represent one of the main causes of drug withdrawal after marketing which would present �besides the health catastrophe- a financial disaster to many of the large pharmaceutical companies. This same cause would describe why searching for a reliable cardiotoxicity detecting system a major need for drug industry (Murphy et al., 2007). 
  
   Cardiotoxicity tests, however, failed to meet this demand, as the in vitro screening systems defects remain the main cause for high rate of drug attrition. The animals derived malignant cell lines carry abnormal karyotype, little array of ion channels and do not resemble the heart phenotypically. On the other hand, primary human cardiac cells are not suitable for large scale use owing to the lack of frequent supply and loss of capability to proliferate efficiently (Denning and Anderson, 2008).

   Embryonic stem cells derived cardiomyocytes were examined for gene expression patterns which revealed normal developement. All the stem cells derived cardiomyocytes expressed cardiac-specific proteins for NP, cTnI, cTnT, MLC-2A, MLC-2V, and myosin heavy chain as well as cardiac-specific genes (NKx2.5, alpha-MHC). The developed cardiomyocytes were further examined for contractile capacity using Microelectrode Arrays (MEAs), this capacity of developing contractions gave us a unique potential of an in vitro 3D heart like structure. (Kehat et al., 2001; Hescheler et al., 2004; Bin et al., 2006). 

     Moreover the developlment of embryonic stem cells derived cardiomyocytes till reaching the mature stage would represent an opportunity to test the developmental toxic effetcs of certain drugs on the heart (Sartiani et al., 2007).     

Neurotoxicity testing:

   Currently, there is no in vitro model for neurotoxicity detection which makes scientists dependent on animal models, an approach which would make us miss a lot due to lake of similarity between complex human traits and the animals. Beside the defects in animal models, an in vitro model seems mandatory to get a clear insight into the pathogenesis and pathways of certain diseases (CIRM, 2008).

   The capacity of different stem cell types to differentiate into neurons would hold a promising approach for applications in neurotoxicity tests. A more important point is the capacity to further differentiate them into more specific subtypes e.g. dopaminergic neurons to test for parkinson's disease inducing agents and the neuroprotective therapies (Collier et al., 2003; Zeng et al., 2007).

Hepatotoxicity testing:
     The discovery of late-stage serious drug induced hepatotoxicity at clinically efficacious doses has led to serious restrictions of the regular use (��black box warning��) of several drugs, including bosentan, trovafloxacin, tolcapone, valproic acid, isoniazid, ketoconazole and felbamate among others. Moreover, recent cases of postmarketing withdrawal of drugs due to hepatotoxicity include tienilic acid, bromfenac, the thiazolidinedione (TZD) insulin sensitizer drug troglitazone (Rezulin) and the antidepressant nefazodone (Serzone) (Pahler and Funk, 2008).

      The liver is considered the ultimate target for a great spectrum of toxins, the availability of large numbers of human hepatocytes is a constant critical demand in toxicology and chemical risk assessment, a need that can not be satisfied using primary human hepatocytes due to limited supply, no doubt then that developing stem cells derived models would be an important need in the field of predictive toxicology (Davila et al., 2004). 
    Hepatic cells derived from embryonic stem cells show hepatic-restricted transcripts and proteins. Hepatocyte-like endodermal markers were also detected in stem cell derivatives. Differentiation and isolation of hepatic-like cells from stem cells was made possible by transfecting stem cells with the reporter gene EGFP fused to an albumin promoter (Wobus and Boheler, 2005). Moreover, the use of epigenetic modulators e.g. histone deacetylases inhibitors would enrich stem cell based hepatotoxicity models. First they can help to trans-differentiate stem cells into hepatocyte like cells and second by using them on malignant stem cells to study their potential (epigenetic modulators) to cure the uncontrolled growth disorders (Snykers et al., 2007).    

Future perspectives
   The fact that embryonic stem cells represent the highest differentiation capacity in all stem cells types would interpret the tendency to use models derived from these high plasticity cells (Sinha, 2005). However, following the debate regarding their ethical dilemmas search for an alternative has begun where iPS would represent the first choice, however recent controversies regarding the validity of their use would slow down this approach (Doi et l., 2009).

    Another choice would be using other stem cells which, despite having lower plasticity, still have the potential to be differentiated into other cell types (Di Gioacchino et al., 2008; Kermani et al., 2008). One of the promising stem cells are the Wharton jelly cells (WJCs) derived from the umbilical cord stroma as they have some degree of resemblance to embryonic stem cells e.g. Oct-4 expression which would support their use as an alternative in modeling systems in place of the highly debated embryonic stem cells (Mitchell, 2006; Karahuseyinoglu, 2007).

   One of the challenges that face stem cell based models would be the end-points or the targets to be monitored. It seems that gene expression changes which represents the response of cell to damage is a more efficient target than simply measuring the damage itself and this would invite the use of toxicogenomics or proteomics (the use of gene expression data for toxic exposure assessment) on accompany with the new stem cell technology (Baharvand et al., 2007). 

Conclusion:
   Stem cell technology is considered a precious new tool in predictive toxicology that can help resolving a lot of problems facing this science, however, many issues need to be settled in order to optimize the capacity of these models including the type of stem used and the end points that we are going to measure for assessment of toxicity . 
References:
Alberio, R., Campbell, K.H.,  Johnson, A. D., 2006. Focus on Stem Cells Reprogramming somatic cells into stem cells. Reproduction 132, 709�720.
Baharvand, H., Fathi, A., Van Hoof, D., Salekdeh, G.H., 2007. Concise Review: Trends in Stem Cell Proteomics. Stem Cells 25, 1888-1903.
Barile, F.A. 2008 Predictive Toxicology and Extrapolation to Human Toxicity. In: Principles of Toxicology Testing. Barille, F.A. (ed.) CRC press N.Y. P.p. 57.
 
 HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bin%20Z%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Bin Z.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sheng%20LG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Sheng, L.G.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gang%20ZC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Gang, Z.C.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hong%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Hong, J.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jun%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Jun, C.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bo%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Bo, Y.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hui%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Hui, S., 2006. Efficient cardiomyocyte differentiation of embryonic stem cells by bone morphogenetic protein-2 combined with visceral endoderm-like cells.  HYPERLINK "javascript:AL_get(this,%20'jour',%20'Cell%20Biol%20Int.');" Cell Biol. Int. 30, 769-776.
Bongso, A., Fong, C., 2009. Human Embryonic Stem Cells: Their Nature, Properties, and Uses. In: Trends in Stem Cell Biology and Technology.  Baharvand, H. (ed.) Humana Press. London, New York, P.p. 1-18.
Brent, J., Klein, L.J., 2007. Common perceived but unproven toxic syndromes. In: Haddad and Winchester's Clinical Managemeent of Poisoning and Drug Overdose. Shannon, M.W., Borron, S.W. and Burns, M.J. (Eds.) Saunders Elsevier, P.P. 1275-1282.

Cezar, G.G., Quam, J., 2007. Embryonic Stem Cells: Innovation in Predictive Toxicology. In: Stem Cell Repair and Regeneration. Habib, N., Levicar, N., Gordon, M., Jiao, L. and Fisk, N. (Eds.)  Imperial College Press, London, P.P.269-284.
Chapin, R.E., Stedman, D. B., 2009. Endless Possibilities: Stem Cells and the Vision for Toxicology Testing in the 21st Century. Toxicological Sciences 112, 17-22.
CIRM 2008. Stem cells in predictive toxicology. California Institute of Regenerative Medicine (CIRM), workshop report, 7�8 July 2008. http://www.cirm.ca.gov/pub/pdf/CIRM_Predictive_Tox. pdf.
Collier, T.J., Steece-Collier, K., McGuire, S., Sortwell, C.E., 2003. Cellular Models to Study Dopaminergic Injury Responses.  Annals of the New York Academy of Sciences 991, 140-151.
D�Inverno, M., Theise, N., Prophet, J., 2006. Mathematical Modeling of Stem Cells: A Complexity Primer for the Stem-Cell Biologist. In: Tissue Stem Cells Potten, C.S., Clarke, R.B., Wilson, J. and Renehan, A.G. (Eds.) Taylor & Francis Group. NY, P.p. 1-5.
Davila, J.C., Cezar, G.G., Thiede, M., Strom, S., Miki, T., Trosko, J., 2004. Use and Application of Stem Cells in Toxicology. Toxicological sciences 79, 214�223.

Denning, C., Anderson, D., 2008. Cardiomyocytes from human embryonic stem cells as predictors of cardiotoxicity. Drug discovery today: therapeutic strategies 5, 223-232.

Di Gioacchino, M., Petrarca, C., Perrone, A., Farina, M., Sabbioni, E., Hartung, T.,  Martino, S., Esposito,D.L. Lotti, L.V., Mariani- ostantini, R., 2008. Autophagy as an ultrastructural marker of heavy metal toxicity in human cord blood hematopoietic stem cells. Science of the total environment 392, 50-58.
Doi, A., Park, I., Wen, B., Murakami, P., Aryee, M.J., Irizarry, R., Herb,B., Ladd-Acosta, C., Rho, J., Loewer, S., Miller, J., Schlaeger, T., Daley, J.Q., Feinberg, A.P., 2009. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nature Genetics 41, 1350 � 1353.
Faustman, E.M., Omenn, G.S., 2003. Risk Assessment. In: Casarett and Doull's Essentials of Toxicology. Klaassen, C.D. and WatkinsIII, J.B. (Eds.) McGraw-Hill N.Y. P.P. 46-58.
Fink, R.D., 2002. Cloning, Stem Cells, and the Current National Debate: Incorporating Ethics into a Large Introductory Biology Course Issues in Development. Cell Biology Education 1, 132-144.
Helma, C., 2005. An introduction to predictive toxicology. In: Predictive Toxicology. Helma, C. (ed.) Marcel Decker, N.Y. P.p. 1.

Heng, B.C., Richards, M., Shu, Y., Gribbon, P., 2009. Induced pluripotent stem cells: a new tool for toxicology screening"? Arch. Toxicol., 83, 641�644.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hescheler%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Hescheler, J.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Halbach%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Halbach, M.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Egert%20U%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Egert, U.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lu%20ZJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Lu, Z.J.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bohlen%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Bohlen, H.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fleischmann%20BK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Fleischmann, B.K.,  HYPERLINK "http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Reppel%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus" Reppel, M., 2004. Determination of electrical properties of ES cell-derived cardiomyocytes using MEAs.  HYPERLINK "javascript:AL_get(this,%20'jour',%20'J%20Electrocardiol.');" J. Electrocardiol. 37, 110-116.
Hodgson, E., 2004. Historical teratogens. In: A Textbook of Modern Toxicology. Hodgson, E (ed.) John Wiley & Sons, P.p. 256.
Karahuseyinoglu, S., Cinar, O., Kilic, E., Kara, F., Akay, G.G., Demiralp, D.O., Tukun, A., Uckan, D., Can, A., 2007. Biology of Stem Cells in Human Umbilical Cord Stroma: In Situ and In Vitro Surveys. Stem Cells 25, 319 -331.
Kehat, I., Kenyagin-Karsenti, D., Snir, M., Segev, H., Amit, H., Gepstein, A., Livne, E., Binah, O., Itskovitz-Eldor, J., Gepstein, L., 2001. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J. Clin. Invest. 108, 407-414.

Kermani, S., Karbalaie, K., Madani, S.H., Jahangirnejad, A.A., Eslaminejad, M.B., Nasr-Esfahani, M.H., Baharvand, H., 2008. Effect of lead on proliferation and neural differentiation of mouse bone marrow-mesenchymal stem cells. Toxicology in Vitro 22, 995�1001.
 
Lin, H., 2008. Cell biology of stem cells: an enigma of asymmetry and self-renewal. The Journal of Cell Biology  180, 257�260.
Magnus, T., Liu, Y.,  Parker, G.C., Rao, M.S., 2008. Stem cell myths. Phil. Trans. R. Soc. B. 363, 9-22.
Mann, R.D., Andrews, E.B., 2002. Introduction. In: Pharmacovigilance Mann, R.D. and Andrews, E.B. (Eds.) John Wiley& Sons, P.P. 3-11.
Mitchell, K.E., 2006. Umbilical Cord Stem Cells In: Contemporary Endocrinology: Stem Cells in Endocrinology. Lester, L.B. (ed.) Humana Press Inc., Totowa, N.J. P.p. 49-65.
Murphy, N.G., Benowitz, N.L., Goldschlager, N., 2007. Cardiovascular toxicology. In: Haddad and Winchester's Clinical Managemeent of Poisoning and Drug Overdose. Shannon, M.W., Borron, S.W. and Burns, M.J. (Eds.) Saunders Elsevier, P.P. 133- 165.

Newall, D.R., Beedles, K.E., 1996. The Stem-Cell Test: an In Vitro Assay for Teratogenic Potential. Results of a Blind Trial with 25 Compounds. Toxicology in Vitro 10, 229-240.

Pahler, A., Funk, C., 2008. Drug-Induced Hepatotoxicity: Learning from Recent Cases of Drug Attrition. In: Advances in Molecular Toxicology. Fishbein, J.C. (ed.) Elsevier P.P. 25-26.

Perla, V., Perrin, N.A., Greenlee, A.R., 2008.  Paraquat toxicity in a mouse embryonic stem cell model. Toxicology in Vitro 22, 515�524.
Rao, M., Condic, M.L., 2008. Alternative Sources of Pluripotent Stem Cells: Scientific Solutions to an Ethical Dilemma. Cells and Development  17, 1�10.
Rohwedel, J., Guan, K., Hegert, C., Wobus, A.M., 2001.  Embryonic stem cells as an in vitro model for mutagenicity,cytotoxicity and embryotoxicity studies: present state and future prospects. Toxicology in Vitro 15, 741�753.
Sartiani, L., Bettiol, E., Stillitano, F., Mugelli, A., Cerbai, E., Jaconi, M.E., 2007. Developmental Changes in Cardiomyocytes Differentiated from Human Embryonic Stem Cells: A Molecular and Electrophysiological Approach. Stem Cells  25, 1136 -1144.
Scholz, G., Pohl, I., Genschow, E., Klemm, M., Spielmann, H., 1996. Embryotoxicity Screening Using Embryonic Stem Cells in vitro: Correlation to in vivo Teratogenicity. Cell Tissues Organs 165, 203-211.
Sinha, G., 2005. Human embryonic stem cells may be toxicology's new best friends. Science 308, 5728.
Snykers, S., Vinken, M., Rogiers, V., Vanhaecke, T., 2007. Differential role of epigenetic modulators in malignant and normal stem cells: a novel tool in preclinical in vitro toxicology and clinical therapy. Arch. Toxicol.  81, 533�544.

Stummann, T.C., Hareng, L., Bremer, S., 2008. Embryotoxicity hazard assessment of cadmium and arsenic compounds using embryonic stem cells. Toxicology 252, 118�122.

Stummann, T.C., Hareng, L., Bremer, S., 2009. Hazard assessment of methylmercury toxicity to neuronal induction in embryogenesis using human embryonic stem cells. Toxicology 257, 117�126.
 HYPERLINK "http://archsurg.ama-assn.org/cgi/content/full/139/1/93" \l "ACK" Sylvester, K.G., Longaker, M.T., 2004. Stem Cells Review and Update. Arch. Surg. 139, 93-99.
Wax, P.M., 2006. Toxicologic Plagues and disasters in history. In: Goldfrank's Toxicologic Emergencies, 8th Edition. Flomenbaum, N. E., Goldfrank, L. R., Hoffman, R. S., Howland, M. A., Lewin, N. A.,  Nelson, L. S.,  (Eds.) McGraw-Hill.

Wobus, A.M., Boheler, K.R., 2005. Embryonic Stem Cells: Prospects for Developmental Biology and Cell Therapy. Physiol. Rev. 85, 635�678.

Zeng, X., Chen, J., Deng, X., Liu, Y.,  Rao, M.S., Cadet, J., Freed, W.J., 2006. An In Vitro Model of Human Dopaminergic Neurons Derived from Embryonic Stem Cells: MPP+ Toxicity and GDNF Neuroprotection.  HYPERLINK "http://www.pubmedcentral.nih.gov/redirect3.cgi?&&auth=0EyD1GbZSYoL0HwCGHVNulxrNrZvQY6hh_2864oQdxH8kC3N9TRpZ-UJZLwgfL2wnwP3XLXzhRU8kA19nanacrsAxf2WpZNEP85iM24LAxHZ7f-JkphmxqPyTC-O1oJIVIlekdoA&reftype=publisher&artid=1852423&iid=143684&jid=319&FROM=Article%7CFront%20Matter&TO=Content%20Provider%7CArticle%7CRestricted%20Access&article-id=1852423&journal-id=319&rendering-type=normal&&http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17109014" \t "pmc_ext" Neuropsychopharmacology  31(12), 2708�2715. 

Zucco, F., De Angelis, I., Testai, E.,  Stammati, A., 2004. Toxicology investigations with cell culture systems: 20 years after. Toxicology in Vitro 18,  153�163.




















 

 
   
./@HI{����	 	7	8	a	b	k	p	O`i��,-������ļϼ������ׇ|n`|`�UGh�-�h�#�6�CJ]�aJh�#�6�CJ]�aJh�-�h�-�6�CJ]�aJh�-�h:�6�CJ]�aJh�S6�CJ]�aJh:�6�CJ]�aJh<JK0JCJaJh<JK>*B*CJaJph�#jh<JK>*B*CJUaJph�h<JKCJaJh<JK5�CJ\�aJh�"CJaJh:�CJaJhkX;5�CJ\�aJh�-�5�CJ\�aJhr�5�CJ\�aJ/IRd}���9	P	a	b	k	��-.�
�
���������������������$dhA$a$gdLt�$dhA$a$gd�aq	$A$a$gdr�	$A$a$gd�#�	$A$a$gd�S$A$gd<JK	$A$a$gd:�	$A$a$gd�-�-012DEm��


�
�
�
�
�
jt��t�����%IKLP��������Ƕ�������zod\d\d\Th�CJaJh&F@CJaJh&F@h&F@CJaJh&F@h��CJaJh��CJaJhLt�CJaJh�j�h�j�5�CJ\�aJh�SCJaJhmmCJaJh�aqh�aq5�CJ\�aJ h&F@h�aq5�6�CJ\�]�aJ h&F@h&F@5�6�CJ\�]�aJh�e�CJaJhr�CJaJh�rOCJaJh�j�CJaJh�aqCJaJ ����IJpq�AB#$kl�*+� ������������������$A$gd<J�$dhA$a$gd�CU$dhA$a$gd�rO$dhA$a$gd<J�$dhA$a$gdg
�$dhA$a$gd�Wn$dhA$a$gd��$dhA$a$gd����������n������23FGH��opq���ºӲ���������p_��Q��Ih<J�CJaJhg
�5�6�CJ\�]�aJ h�rOhg
�5�6�CJ\�]�aJ h�rOh�rO5�6�CJ\�]�aJh�rOCJaJh�e�CJaJhg
�CJaJ hj<hhj<h5�6�CJ\�]�aJhj<hCJaJh��CJaJh��CJaJ h��h��5�6�CJ\�]�aJh&F@h��CJaJ h�h��5�6�CJ\�]�aJ h�h�5�6�CJ\�]�aJq��FG^`��&@BQR����01r|��eq��!"$�������횐�����y�l�l�l�\�N�h<J�5�6�CJ\�]�aJh<J�5�6�OJQJ\�]�^Jh<J�6�CJPJ]�aJh<J�h<J�CJPJaJhS�CJPJaJh�rOCJPJaJh<J�CJPJaJ h/�h<J�5�6�CJ\�]�aJh<J�6�CJ]�aJh<J�5�6�CJPJ\�]�aJ$h/�h<J�5�6�CJPJ\�]�aJh<J�CJPJaJh<J�CJaJh<J�5�CJ\�aJ$^j�������
5;���*+_ � � � � � � � � �����ȺȺȺȺ۩ۗ�|p|[I[|p|"h�Wn5�6�CJ\�]�aJmHsH(h/�h<J�5�6�CJ\�]�aJmHsHh�U�CJaJmHsHh<J�CJaJmHsHh<J�5�CJ\�aJmHsH"h<J�h<J�6�CJ]�aJmHsH h/�h<J�5�6�CJ\�]�aJh�^Zh<J�6�CJ]�aJh�^Zh<J�CJaJh�CUCJaJh<J�CJaJ$h/�h<J�5�6�CJPJ\�]�aJh<J�CJPJaJ� � ""V"$$v&w&�&�'�'�)�)R+S+e-����������������$dhA$a$gd��$dhA$a$gdj�$dhA$a$gd�w-$
&F���dhA$a$gd�k~$dhA$a$gdC8�$dhA$a$gd��$dhA$a$gd�U�$dhA$a$gd�CU	$A$a$gd<J�� � � 	!!!!�!�!�!�!
"""U"V"Z"p"�#�#�#�#�������ͺ���qbVJVJ�J>h��CJaJmHsHhC8�CJaJmHsHh�U�CJaJmHsHh�U�6�CJ]�aJmHsH"h�U�5�6�CJ\�]�aJmHsH"h<J�5�6�CJ\�]�aJmHsH(h/�h<J�5�6�CJ\�]�aJmHsHh�U�B*CJaJmHphsH%h�],h<J�B*CJaJmHphsHh�U�B*CJaJphh�],h<J�B*CJaJphh<J�CJaJmHsHh�CUCJaJmHsH�#�#�#�#�#$$$.$W$X$�$�$�$�$�$�$�$��������r�UCU�4�hZ.�hZ.�B*CJaJph#hZ.�h��5�B*CJ\�aJph8hZ.�h��0J5�B*CJ\�aJfHphq�
���� hZ.�h��B*CJH*aJphhZ.�h��B*CJaJph%hZ.�h��B*CJaJmHphsHh�e�B*CJaJmHphsHh��CJaJmHsHh�U�CJaJmHsHhC8�CJaJmHsH"h�rO5�6�CJ\�]�aJmHsH(hC8�hC8�5�6�CJ\�]�aJmHsH�$�$�$�$�$�$�$�$�$�$%%%"%#%=%>%?%a&u&v&w&�&o'����������䕃nY��n�M>MhC8�5�CJ\�aJmHsHhC8�CJaJmHsH)hZ.�h��5�6�B*CJ\�]�aJph)hZ.�hZ.�5�6�B*CJ\�]�aJph#hZ.�hZ.�6�B*CJ]�aJph#hZ.�h��6�B*CJ]�aJph8hZ.�h��0J5�B*CJ\�aJfHphq�
����hZ.�hZ.�B*CJaJph hZ.�h��B*CJH*aJphhZ.�h��B*CJaJphh�CUB*CJaJpho'p'�'�'�'{))�)�)�)�)�)
*
*&*�*�*;+P+Q+R+�+�+�,�,�,M-c-e-f-h-�-�-H.����������������m���a�U�h�,CJaJmHsHh��CJaJmHsH"h{S�5�6�CJ\�]�aJmHsH(h��h��5�6�CJ\�]�aJmHsHh{S�CJaJmHsHh��CJaJmHsH(h�w-h�w-5�6�CJ\�]�aJmHsHh�w-CJaJmHsHh�k~CJaJmHsHh�k~6�CJ]�aJmHsHhC8�CJaJmHsHhj�CJaJmHsH!e-f-�.�.�0�0�1�1�13355j7�������������$dhA$a$gd`t$dhA$a$gd&z$dhA$a$gd?~�$dhA$a$gd�U�$
&F���dhA$a$gd�^Z$dh7$8$A$H$a$gd{S�$dh7$8$A$H$a$gdj�$dhA$a$gd{S�$dhA$a$gd��
H.�.�.�.�.�.�.�.�.�.�.�./�/�/�/�/�/�/�/�/000&0d0e0�0�0�0�0l1����ǻǬ�������s�f\f\f\f\f\fR\hj�CJPJaJh=�CJPJaJh=�hg�CJPJaJh=�CJaJmHsH(h��h��5�6�CJ\�]�aJmHsHh��CJaJmHsHhj�CJaJmHsHh=�hg�CJaJmHsHh{S�CJaJmHsHhg�CJaJmHsHh��CJaJmHsH(h��h��5�6�CJ\�]�aJmHsHh��CJaJmHsHl1�1�1�1�1�1�1�1�2�23333T3U3w33�3�3�3�45C5���̽����{�l�`�`�`T`T?T(h&zh&z5�6�CJ\�]�aJmHsHh&zCJaJmHsHh?~�CJaJmHsHh�U�h�^ZCJaJmHsH(h�U�h�U�5�6�CJ\�]�aJmHsH(h�U�h�^Z5�6�CJ\�]�aJmHsHh�rOCJaJmHsHh�^ZCJaJmHsHh�^Z6�CJ]�aJmHsHh�h�CJPJaJh{S�CJPJaJh=�CJPJaJ$h=�h=�5�6�CJPJ\�]�aJC5�5�5�5�5�566L6M6P6Q6)7g7h7i7j7p7�7�7=8T8U8V8Z8[8�����������������p�aUFh�^Zh?~�CJaJmHsHh?~�CJaJmHsHh"ih?~�CJaJmHsH(h"ih"i5�6�CJ\�]�aJmHsHh�rOCJaJmHsHh`th�rOCJaJh"iCJaJmHsHh&zCJaJmHsH(h&zh&z5�6�CJ\�]�aJmHsHh`tCJaJmHsHh`th`tCJH*aJh`tCJaJh`th`tCJaJhZVCJaJmHsHj7k7[8\8s8t8::�;�;�;�=����������r$dh7$8$A$H$a$gd{S�$
&F���dhA$a$gd�S�$dhA$a$gd�S�$dhA$a$gd{S�$dhA$a$gd@�$dhA$a$gd�"H$dhA$a$gd"i$
&F���dhA$a$gd"i$dhA$a$gd<J�$dhA$a$gd�rO[8\8t8w8R9�9�9�9:::A;c;d;�;�;�;�;�;�;�;�;�;H<I<�<�<�<�<==N=O=�=�=�=�=�����̾���坶嶒�|q�qiqiqaqiqiqiqah�CJaJh�CJaJh�h�CJaJh$
�h?=�CJaJh$
�h�S�CJaJh�S�6�CJ]�aJ h�S�h�S�5�6�CJ\�]�aJh{S�CJaJh�S�CJaJh�"H5�6�CJ\�]�aJ h@�h@�5�6�CJ\�]�aJh"iCJaJh@�CJaJh"i6�CJ]�aJh<J�CJaJ$�=�=�=�=�=�=2>�>?�?�?�?�?�?�?�?�?�?�?�?@@7@;@@@P@R@S@�@�@�@�@�@��������n�f^S^SfS^Sf^fS^S^S^Sh�~�h�~�CJaJhg�CJaJh�~�CJaJ h$
�h�S�5�6�CJ\�]�aJ h$
�h�RK5�6�CJ\�]�aJh$
�h�RKCJaJh$
�CJPJaJh$
�h$
�CJPJaJh$
�h�S�CJaJh{S�CJaJh�CJOJQJ^JaJh�h�CJaJ h�h�5�6�CJ\�]�aJ h�h�5�6�CJ\�]�aJ �=�=�?�B�B�BzD{D�F�F�H�H�H�I�I�JK����������������$�d�d7$8$A$H$[$\$a$gd�+{$dhA$a$gd�RV$dhA$a$gd��$dhA$a$gdw*�$dhA$a$gdzO&$dhA$a$gd�RK$dh7$8$A$H$a$gdg�$dh7$8$A$H$a$gd��@�@�@�@�@�@AAGAxB�B�B�B�B�B�B�B�B�BiCjCwCxCODXDfDgD������ɼ����������{jY�Q�Ihw*�CJaJhzO&CJaJ h��h�RK5�6�CJ\�]�aJ h��h��5�6�CJ\�]�aJh��CJaJhZVCJaJh�RK5�CJ\�aJh�RKCJaJh$
�h�S�CJaJ$h$
�h?=�5�6�CJPJ\�]�aJh$
�h?=�CJPJaJh$
�h?=�CJaJ hg�hg�5�6�CJ\�]�aJh�~�CJaJh�~�h�~�CJaJhg�CJaJgDyDzD{D�D�D�D�D�D�DEEEME�F�F�F�F"G#G�G�G�GHHgHhH�H�H�H�H�H�H�HcI{I�I�I�I����������ɻ�����⣛�����y�n�f�f�f�h:�CJaJh�RV5�CJ\�aJ h��h�5�6�CJ\�]�aJ h��h��5�6�CJ\�]�aJh��CJaJh�CJaJh�RVCJaJhf�CJaJh!j=5�6�CJ\�]�aJ h$;
h$;
5�6�CJ\�]�aJhzO&CJaJhw*�CJaJh$;
CJaJhw*�5�6�CJ\�]�aJ&�I�IJJ"J$J(J*JiJjJ{J|J�J�J�J�J�J�J�J�J�J�J�J�J�J�J�J�J�J�JKK
KKK������ŶŶŶ���v�v�v�vňY�Y�ňň��8h�8�h��0J5�B*CJ\�aJfHphq�
����#h�8�h��5�B*CJ\�aJphh�8�h��B*CJaJph!h�8�h��0JB*CJaJphh�8�0JB*CJaJphh�8�h�BAB*CJaJphh�+{B*CJaJphh�+{5�B*CJ\�aJph#h�8�h�BA5�B*CJ\�aJphh��5�6�CJ\�]�aJ"KK KYKZKK�K�K�K�K�KgLhLmLnLoLqLrL,M-M2M3M5M6M7M8M9M;M<M�M�M�M�M�M�M�MNNNN�N�N�N�N�N�N�N�N�N�O�O�O�O������ѽѦ������������������������������������������h�+{5�B*CJ\�aJph#h�8�h'y5�B*CJ\�aJph,jh�8�h'y5�B*CJU\�aJphh�8�CJPJaJh�+{CJPJaJh�8�h�BACJPJaJh�8�h�BAB*CJaJph#h�8�h�BA5�B*CJ\�aJph4K�K�K	R�R�S�S�T\UV�V�W����������l$�d�d7$8$A$H$[$\$a$gd�1�$�d�dA$[$\$a$gd�1�$�d�d7$8$A$H$[$\$a$gd�8�$�d�d@&A$[$\$a$gd�+{
$7$8$A$H$a$gd�+{$�d�d7$8$A$H$[$\$a$gd�+{$
�l7$8$A$H$a$gd�+{	$A$a$gd�8�	$A$a$gd�+{�O�O�O�O�O�OBPCPEPFPHPIPJPLPMPQQQ	QQQ
QQQQQ�Q�Q�Q�Q�Q�Q�Q�Q���������������������Ǽ������t�a�$h�8�h'y0J>*B*CJaJph!h�8�h'y0JB*CJaJph*jh�8�h'y0JB*CJUaJphh�8�h'yCJaJh�+{CJaJh�8�h'y5�CJ\�aJh�+{5�CJ\�aJh�+{5�B*CJ\�aJph,jh�8�h'y5�B*CJU\�aJph#h�8�h'y5�B*CJ\�aJph!�Q�QRR	RRRR#R$R%RcR�R�R�R�R�R�R�R�R�R�R�R�R S!S�S�S�S����͹͹��������m^m^mOOOh�8�h'yB*CJaJphh�+{5�B*CJ\�aJph#h�8�h'y5�B*CJ\�aJphh�+{B*CJaJphh�8�h�BAB*CJaJph!h�8�h�BAB*CJPJaJphh�+{B*CJPJaJph'h�8�h�BA5�B*CJPJ\�aJph!h�+{5�B*CJPJ\�aJphh�8�h'yCJaJh�+{0JCJaJh�8�h'y0JCJaJ�S�S�S�S�S�S�S�S�S�S T!T&TRTST_T`TkTlT�T�T�T�T�T�T�T7UUU\UaU�������ø����øøø�����teteT!h�1�5�B*CJPJ\�aJphh�8�h'yB*CJaJphh�+{B*CJaJphh�+{5�B*CJ\�aJph#h�8�h'y5�B*CJ\�aJphh�+{CJPJaJh�8�h'yCJPJaJh�8�h'yCJaJh�+{CJaJh�+{5�CJ\�aJh�8�h'y5�CJ\�aJh�8�h�+{B*CJaJphh'yB*CJaJphaUeUfUV"V)V<V=VIVJVYV[V_VaV�V�V�V�V�V�V�V�V�V�V�V�V�VWyWzW�W�W�W��ɷ����������y����g�g�g�g�X�X�Xh�8�h�BAB*CJaJph#h�8�h�BA5�B*CJ\�aJph'h�8�h'y0J6�B*CJ]�aJphh�8�h'yB*CJaJphh�1�B*CJaJphh�1�5�B*CJ\�aJph#h�8�h'y5�B*CJ\�aJph!h�8�h'yB*CJPJaJph!h�1�5�B*CJPJ\�aJph'h�8�h'y5�B*CJPJ\�aJph �W�W�W�W�W�W�WXX
XXXXXX XRXiXkXlXmXuXvXwX�X�X�X�X�X�X�XYY!Y"Y��������������·���𪢚�y�y�y�n�nch�8�5�CJ\�aJh�8�h�8�CJaJh�1�5�B*CJ\�aJph#h�8�h�8�5�B*CJ\�aJphh�8�CJaJh�BACJaJh�8�h�BACJPJaJh�8�h�BACJaJh�1�CJaJh�1�5�CJ\�aJh�8�h�BA5�CJ\�aJh�1�5�CJPJ\�aJh�8�h�BA5�CJPJ\�aJ"�WvXwX!Y"YXZ�[~\>]�]�]Z^�d+ef��������������$�d�d@&A$[$\$a$gd:�$�d�d@&A$[$\$a$gd�1�$�d�d7$8$A$H$[$\$a$gd�1�$�d�dA$[$\$a$gd�1�
$7$8$A$H$a$gd�1�
$7$8$A$H$a$gd�8�	$A$a$gd�8�	$A$a$gd�1�"Y3Y4YAYBYNYOYZY[YhYiYuYvY�Y�Y�Y�Y�Y�Y�Y�Y
Z)ZOZPZWZXZ_Z`ZiZjZrZsZ�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z[[[�������������������������ů����������������������������%h�1�5�B*CJ\�aJmH	phsH	+h�8�h�BA5�B*CJ\�aJmH	phsH	h�8�h'yB*CJaJphh�8�h'yCJaJh�1�CJaJh�1�5�CJ\�aJh�8�h'y5�CJ\�aJ7[	[�[�[�[�[�[�[�[�[\\~\�\�\�\�\�\1]3]4]>]G]H]M]N]�]�]�]�]�]�]�]�]�]�]�]�]��ͻ�����������������������xmxmxmxmxeh�1�CJaJh�1�5�CJ\�aJh�8�h'y5�CJ\�aJh�8�5�CJ\�aJh�8�h'yB*CJaJphh�1�B*CJaJphh�1�5�B*CJ\�aJph#h�8�h'y5�B*CJ\�aJphh�8�h�BAB*CJaJph%h�8�h�BAB*CJaJmH	phsH	h�1�B*CJaJmH	phsH	%�]=^P^X^Z^[^__"_#_%_&_'_)_*_�_�_�_�_�_�_�_�_�_�`�`�`�`�`�`�`�`�`satavawayaza{a|a}aa�a:b;bAbBbDbEbFbHbIb	c
cccccccccc�c�c���ǵǵ��Ǧ�ǵǵ��Ǧ�ǵǵ��Ǧ�ǵǵ����Ǧ�ǵǵ��Ǧ�ǵǵ����Ǧ�ǵ�h�1�5�B*CJ\�aJph#h�8�h'y5�B*CJ\�aJph,jh�8�h'y5�B*CJU\�aJphh�8�h'yCJPJaJh�1�CJPJaJh�8�h'yCJaJA�c�c�c�c�c�c�c�c�cAdBdCd�d�d�d�d�d�d�d�d�d�d�d�d�d+e>e?eIe�����������m���c��UJUJ����h�1�5�CJ\�aJh�8�h'y5�CJ\�aJh�1�0JCJaJ$h�8�h'y0J>*B*CJaJph!h�8�h'y0JB*CJaJph*jh�8�h'y0JB*CJUaJphh�8�h'y0JCJaJh�8�h'yCJaJh�1�CJaJ,jh�8�h'y5�B*CJU\�aJphh�1�5�B*CJ\�aJph#h�8�h'y5�B*CJ\�aJphIeJeTeUe^e_ejekeze{e�e�e�e�e�e�e�e�e�e�e�e�e�e�efffff.f/f8f9fCfDfMfNf[f\fffgfqfrf�f�f�f�f�f�fg)g���������������������÷÷é�����������������������h�8�h'yCJaJh:�CJaJh:�5�CJ\�aJh�1�5�CJ\�aJh�8�h'y5�CJ\�aJh:�B*CJaJphh�8�h'yB*CJaJphh�1�B*CJaJph#h�8�h'y5�B*CJ\�aJphh�1�5�B*CJ\�aJph2)g2g4g?g@gNgOg\g]gqgrg�g�g�g�g�g�g�g�g�g�gh.h/h8h:h;h<hChDhEhIhJhoh�h�h�h�h�h�h����������������ܺ������z�z�k�k�k��h�8�h'yB*CJaJphh:�5�B*CJ\�aJph#h�8�h'y5�B*CJ\�aJphh�8�CJaJh:�CJaJh�8�h�8�B*CJaJphh:�B*CJaJphh:�5�CJ\�aJh�1�5�CJ\�aJh�8�h�8�5�CJ\�aJh�8�h�8�CJaJh�8�h'yCJaJ'f3g4g:h<h�h$i�iVjMkNk�kl�l�lAm���������������
$7$8$A$H$a$gd�8�	$A$a$gd�8�	$A$a$gd:�$�d�d7$8$A$H$[$\$a$gd:�
$7$8$A$H$a$gd:�$
�l7$8$A$H$a$gd�8�$
�l7$8$A$H$a$gd:��h�h�h�h�h�h�h�h�h�hii$i.i/i=i>iCiDi�i�i�i�i�ijUjVjbjcjrjsj�j�j�j�jk��������ôô�ϢϢÓ�ρ�rar��ρρ�r!h�8�h�8�B*CJPJaJphh�8�h�8�B*CJaJph#h�8�h�8�5�B*CJ\�aJphh�8�hmmB*CJaJph#h�8�hmm5�B*CJ\�aJphh�8�h'yB*CJaJphh:�B*CJaJphh:�5�B*CJ\�aJph#h�8�h'y5�B*CJ\�aJphh�1�5�B*CJ\�aJph#kkNk[kikjkokpk�k�k�k�klllllllel�l�l�l�l�l�l�l�l�l�l6m7m?mAm������ø�ø��{�{o���d�����øøUh�8�h'yB*CJaJphh�1�5�CJ\�aJh:�B*CJaJph#h�8�h�8�5�B*CJ\�aJphh:�5�B*CJ\�aJphh�8�h�8�CJaJ h�8�h'y5�6�CJ\�]�aJh�8�h'yCJaJh:�CJaJh�8�h'y5�CJ\�aJh:�5�CJ\�aJh�8�h�8�B*CJaJphh�1�B*CJaJph!AmImPmQmVmXm\m]m�m�m�m�m�m�m�m�m�m�m�m�m	n
nnnyn�n�n�n�n�n�n�n�n�n�n�n�n�n�nooo������ппп�����������y�y�y�j�j�j�j�����h�1�5�B*CJ\�aJphh�8�h�8�CJaJh:�CJaJh:�5�CJ\�aJh�1�5�CJ\�aJh�8�h�8�5�CJ\�aJh�8�h�8�B*CJaJph!h�8�h�8�B*CJPJaJphh:�B*CJPJaJph#h�8�h�8�5�B*CJ\�aJphh:�5�B*CJ\�aJph)Am�m�n�o�p�p�q�qyrzr6s�s�t�tZu[uWxXx�x�x�x��������������������	$A$a$gd�q|	$A$a$gd�8�
$7$8$A$H$a$gd�8�$�d�d@&A$[$\$a$gd:�
$7$8$A$H$a$gd:�$�d�dA$[$\$a$gd:�oo�o�o�o�o�o�o�o�o�o�o�o�o�o�o�o�o�o�o]pxpp�p�p�p�p�p�p�p�p�p�p�p�p
qqqqq q!q�q�q�q�q�q�q�q���������������֦�����֦����������֛��䑄�h�8�h�8�CJPJaJh:�CJPJaJh�8�h�8�CJaJh:�CJaJ#h�8�h�8�5�B*CJ\�aJphh:�5�CJ\�aJh�1�5�CJ\�aJh�8�h�8�5�CJ\�aJh�8�h�8�B*CJaJphh:�B*CJaJph0�q�q�q�q�q�q�q�qrrr^r_rnrorxryrzr�r�r�r�r�r�r�rs+s,s4s6s7s�s�s�s�s�s�s�s�s�s�s�s�s�����޴�����������޴�����l�l��l�޴����,jh�8�h�8�5�B*CJU\�aJphh�8�h'yB*CJaJphh:�CJaJh�8�h�8�CJaJh�8�h�8�B*CJaJphh:�B*CJaJphh:�5�B*CJ\�aJphh�1�5�B*CJ\�aJph#h�8�h�8�5�B*CJ\�aJphh�8�5�B*CJ\�aJph*�s�s�s�s�s�st&titjt{t|t�t�t�t�t�t�t�t�t�t�t�t�t�t�t�t�t�t�tu=uLuMuOuPu[ucudumunuwuxu�u�u�u�u�u�u�u�u�u�u�u�uv�������ļļļĴ�ĴĴ������ĴěĴ���������ě�h�1�5�CJ\�aJh�8�h�8�6�CJ]�aJh�q|5�CJ\�aJh�q|CJaJh�1�CJaJh�8�h�8�CJaJh:�CJaJh:�5�CJ\�aJh�8�h�8�5�CJ\�aJh�8�h�8�B*CJaJph7vv'v(v(x)xHxIxUxVxXxaxbxqxrx}x~x�x�x�x�x�x�x�x�x�x�x�����Ź��ŧ��������}ncTcLch�q|CJaJh�8�hLt�B*CJaJphh�8�hLt�CJaJh�8�hLt�B*	CJaJphch�q|B*	CJaJphch�q|5�B*CJ\�aJphh�1�5�B*CJ\�aJph#h�8�hLt�5�B*CJ\�aJphh�q|B*CJaJphh�8�h�8�B*CJaJph&jh�8�h�8�B*CJUaJphh�8�h�8�CJaJh�8�h�8�CJH*aJ�x�x�x�xyyyyyyyy	y
yyy
y�����peZOD5�h�8�h�B*CJaJphh�8�h�CJaJh�8�hnr�CJaJh�8�hg�CJaJh�8�h�\�CJaJh�8�h	,#B*CJaJphh�8�h!j=B*CJaJphh�8�h�8�5�CJ\�aJh�8�h�"HB*CJaJphh�8�h�\�B*CJaJphh�8�h�9CJaJh�8�hN"*5�CJ\�aJh�8�h�95�CJ\�aJh�8�h�9B*CJaJphh�8�h�,B*CJaJph�x�x�xyyyyyyyy	y
yyy
yyyyyyyy����������������������	$A$a$gd�8�$
�l7$8$A$H$a$gd�8�
$7$8$A$H$a$gd�8�
yyyyyyyyy���ø���h�8�h"iCJaJh�8�h@�CJaJh�8�h$;
CJaJh�8�hf�CJaJh�8�h��B*CJaJphh�8�hmmB*CJaJphh�8�h�U�B*CJaJphh�8�h�	AB*CJaJph81�h:pkX;��. ��A!�"�#��$��%�������(2*2b���������666666666vvvvvvvvv666666>666666666666666666666666666�6666666666�666666666666hH66666666666666666666666666666666666666666666666666666666666666666�62���� 0@P`p������2(�� 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p��8X�V~PJ_HmH	nH	sH	tH	R`�RNormal$��A$CJ_HaJmH	nHsH	tHT@"T�9	Heading 2$�d�d@&A$[$\$5�CJ$\�aJ$DA`�DDefault Paragraph FontRi�RTable Normal�4�
l4�a�(k �(No List*W@��*��Strong5�\�4U@�4�9	Hyperlink	>*ph��O��9ti.X@�!.�"HEmphasis6�]�B��1B�"Hcitation-abbreviationJ��AJ�"Hcitation-publication-date6��Q6�"Hcitation-volume4��a4�"Hcitation-issue8��q8�"Hcitation-flpages\�O�\�"Hcontent$�d�dA$[$\$B*CJOJQJ^JaJphL��L�"Htitle201#5�CJOJQJ\�^JaJo(ph����&F@lkPK!����[Content_Types].xml���N�0E�H���-J��@%�ǎǢ|�ș$�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"/>q
�����-�q$� �#�$o'H.l1C5[8�=�@gD�IK�O�Q�SaU�W"Y[�]�cIe)g�hkAmo�q�sv�x
yy=?ABCEFGHJKLNOQRSTVWXYZ\]^_`acdeghijkm�� e-j7�=K�WfAm�xy>@DIMPU[bfl�7�CgDmDqD,E7E;E�E�EF�F�F�F�G�G�GBHHHLHII�I�I�IZVW%W)W�W�W�W�X�X�XsY{YY:ZDZHZ	[[[�[�[B\�\�\6k�k�k'n(pUpqX��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X��X���8�@�����������0�(	�
��B
�S����	?���
_Hlt252300862Tpq@Tpq��&U)V)W)X)Y)Z)[)\)])^)_)`)a)b)c)d)e)f)g)h)i)j)k)l)m)n)o)p)q)r)s)t)u)v)w)x)y)z)���BB�J�J�J1K1KsK�L�L�L�L�L�N�N�N�O�O�O�OaTaTmT^=b=bEb�b�b�b�f�fg�gopq	

 "!#$%���BB�J�J�J;K;KzK�L�L�L�L�L�N�N�N�O�O�O�OlTqTqT^CbIbIb�b�b�bggg�gqpq	

 "!#$%8"*�urn:schemas-microsoft-com:office:smarttags�City�9*�urn:schemas-microsoft-com:office:smarttags�State�9&*�urn:schemas-microsoft-com:office:smarttags�place�=%*�urn:schemas-microsoft-com:office:smarttags	�PlaceName�=$*�urn:schemas-microsoft-com:office:smarttags	�PlaceType�5�&%$&"&"&"&&%$&"&%$&"&"&"&&"&"&&"&&:@]c������u{[gw���������F	O	�
�
�
�
ot4
8
�
�
HN*1�!%/;Feq��������*0_`��������	
LO���������
UZ�����.bgw��op��a b ! !!�!�!�!�!�!"!"&"'"�"�"# #;#<#P#U#�#�#�$�$�$�$M%N%c%i%!&"&�&�&�&�&�&�&�&�&''�'�'�'m)r)�)�)�)�*�*�*�*++T+V+w+x++�+�+�+�,�,--�-�-�-�-�-�-�-M.P.Q.)/*/g/p/�/�/=0>0T03)3J3Y3{33t4|4~4�4�4�4�4�4�4�4�4555=5D5M5�5�5�5�5�5�5�5�5�5�5�8999O9[9y:�:k;p;�;�;h<k<=(=7=>=�=�=�>�>�?�?i@r@�A�A�B�B�B�B�B�BCC�C�CIII,I	JJ�J�JGKRK�K�K�K�KILNLTL[LNN*N0NKNSN�N�N�N�NmOsO�O�O�O�O�O�OPP�P�P�P�P%Q/Q5Q=QCQJQ\QdQjQqQ�Q�Q�Q�Q�Q�Q�Q�Q�Q�QXR[R\R_RaRiRkRrRtR�R�R�R�R�R�R�R�R�R�R�R�R�R�R�R�R�R�R�R�RSSS
S�S�S�S�S�S�S�STTTT6T>TITST>UCU�U�U�U�U�U�U�U�UCVJVW"W�W�W�X�X�[�['\5\<\A\�\�\+]:]@]E]K]P]`]d]l]t]|]�]�]�]�]�]^^^*^0^4^:^?^E^I^O^W^]^b^h^m^s^�^�^�^�^�^____4_;_A_J_P_V_^_k_s_~_�_�_�_�_``�`�`Wahadblbtb�b�b�bc
cNcTc\ccc�c�cdd�d�d�d�d�d�dAeDeJePe�e�e�e�e�ef@fYf^flf�f�f�f�f�f�f�f�f�f�f�fg,g:g�g�g�g�g�g�g�g�g�gh�h�h�h�h�h�h�hiii�i�i�i�i�i�ijjzj�j�j�j�k�k�k�k&l1l2l=lXlblkltl�l�l�l�l�l�l[m_m�m�mn%n)p@pXp]pspyp�p�pq��&aj���)0��UZ��w�������!�!Q#U#d%i%�&�&�'�(�(�)�)�)++
--�-M.i/p/Z0l<n<BBCZC�C�C�J!K�L�L\MfMNNN`NaN�N�NO�O P!PQPRPuP�P�PuQQ�Q*R+RWR�R�ROUxU�U�U�[�\�\�\+]�]�]
^^�^4_�_�_``9`�`�`�`�`EaRa�b�b�c�c�d�d�deAe]e�e�eLfYf�fg�g�g�g�g�h�h�jk�k�k�k�k�k!l�m�m)pDp}p�p�p�pq33333333333333333333333333333333333333333333333333333333/I��9abpq����)�)\0w0�3�3�@�@�A�A[C�C"LIL!PRP�\�\�]^�`aEaSa�b�b�k�k�pqq@H���)�)�A�Aq�4u2�4�����������������^��`���6o(-�
�������^��`����h�H.�
�p�L��p^�p`�L��h�H.�
�@����@^�@`����h�H.�
�����^�`����h�H.�
���L���^��`�L��h�H.�
�������^��`����h�H.�
�������^��`����h�H.�
�P�L��P^�P`�L��h�H.�4u�����������								 �]F�?5�+-_9���]
�	�E�T��i�&@"F�a+15#J3^:�%�^;`2&&�i�&�m�(QJ�{�
@*-['4'c o�5^:�%�&�6�
@*/69+-_9xb�^;`2&&�LC>�#T8D�T�K�D�	�E['45#J�LC>�#T�m�(�@�_�]xb�D��j8D'c o?5�0)�ta+1QJ�{3Q�P$;
�,�"��	,#K#zO&N"*�w-�}6�9kX;!j=&F@�	A�BA�"H<JK�RK�rOtS�S�CUZV�RV�^ZTaj<h"imm�Wn�aq`t'y&z�+{�q|�k~�-���@�y��1��U�r����~�Z.�f����S�S��h� 7�C8��w*�:��e����#�nr�Lt�{S��U�g
�<J����8�?~�=�g�$
��j�j����\���?=�:�qq�@qh@��Unknown������������
G��*�Ax�	�Times New Roman5��Symbol3.��*�Cx�	�Arial[��TimesNewRomanPSMS MinchoS��Times-RomanMS Minchoi�Times-BoldItalicTimes New Roman]��TimesLTStd-RomanMS MinchoS�AdvBmTimes New Roman;���(SimSun�[SOA���$B�Cambria Math"q����h���ƭ�'$��8`9��8`9�!������24�p�p	3�Q� ��HX	�?����������������������kX;2!	xx����$Predictive toxicology and stem cellsUSERMido����Oh��+'��0��������	(
HT
`lt|��(Predictive toxicology and stem cellsUSERNormalMido36Microsoft Office Word@�'d@Ծ�j��@�B�U��8`����՜.��+,��D��՜.��+,��Php|�������
����9�p%Predictive toxicology and stem cellsTitle` 8@_PID_HLINKS�Ar*T6�http://www.pubmedcentral.nih.gov/redirect3.cgi?&&auth=0EyD1GbZSYoL0HwCGHVNulxrNrZvQY6hh_2864oQdxH8kC3N9TRpZ-UJZLwgfL2wnwP3XLXzhRU8kA19nanacrsAxf2WpZNEP85iM24LAxHZ7f-JkphmxqPyTC-O1oJIVIlekdoA&reftype=publisher&artid=1852423&iid=143684&jid=319&FROM=Article%7CFront%20Matter&TO=Content%20Provider%7CArticle%7CRestricted%20Access&article-id=1852423&journal-id=319&rendering-type=normal&&http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=17109014
37http://archsurg.ama-assn.org/cgi/content/full/139/1/93ACKF206javascript:AL_get(this, 'jour', 'J Electrocardiol.');I-�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Reppel%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus|%*�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Fleischmann%20BK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusA	'�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bohlen%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusY$�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lu%20ZJ%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusy<!�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Egert%20U%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusI�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Halbach%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus/�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hescheler%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPluse3javascript:AL_get(this, 'jour', 'Cell Biol Int.');
\�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hui%20S%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusL�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bo%20Y%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus\�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jun%20C%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus(n�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Hong%20J%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus5r	�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Gang%20ZC%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusJ�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Sheng%20LG%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus@�http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Bin%20Z%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusTsmailto:toxicsalama@hotmail.com	

 !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmn����pqrstuvwxyz{|}~������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������Root Entry��������	�F�}��U���1Table��������o>@WordDocument��������:�SummaryInformation(�����DocumentSummaryInformation8��������������CompObj������������r������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������
����	�F Microsoft Word 97-2003 Document
MSWordDocWord.Document.8�9�q

Youez - 2016 - github.com/yon3zu
LinuXploit