����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 : 172.69.214.60
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/Jan/27/

Upload File :
current_dir [ Writeable ] document_root [ Writeable ]

 

Command :


[ Back ]     

Current File : /efsdata/authorproof.omicsgroup.co.in/paper-submissions-new/2021/Jan/27/body-1611730677.doc
��ࡱ�>��	�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������y�	���bjbj��	4��{�{#f�������rr�������������,4��?�@@@@@///�>�>�>�>�>�>�>$tB�&EX!?i�/////!?��@@��?.../r
�@�@�>./�>..V1@�1@����p��)z�������+&W1�>�?0�?c10~E�-�~E�1�1\~E��1�//./////!?!?.///�?////��������������������������������������������������������������������~E/////////r �:	@Journal of Molecular Biomarkers & Diagnosis
Short name: J Mol Biomark Diagn
Volume 12: 1, 2021	
Covid-19 Spreading Across World Correlates with 677T Allele of the Methylenetetrahydrofolate Reductase (MTHFR) Gene Prevalence
Giovanni Ponti1*, Lorenza Pastorino2, Gabriella Oliva3, Tomris Ozben4, Marco Manfredini5 , Shaniko Kaleci6, Nicoletta Lelli7, Raffaele Iannella1, Aldo Tomasi1
�Division of Clinical Pathology, Department of Surgical, Medical, University of Modena and Reggio Emilia, Modena, Italy
2Department of Genetics, University of Genoa, Italy
3Internal Medicine, Ospedale del Mare, Asl Napoli1, Naples, Italy
4Department of Clinical Biochemistry, Medical Faculty, Akdeniz University, Antalya, Turkey
5Dermatology Unit, University of Modena and Reggio Emilia, Modena, Italy
6Department of Surgical, Medical, University of Modena and Reggio Emilia, Modena, Italy
7Department of Laboratory Medicine, OCSAE, Azienda USL of Modena, Modena ItalyIndia
Abstract
Homocysteine assessment has been proposed as a potential predictive biomarker for the severity of COVID-19 infection. The purpose of this review was to analyze the correlation between the prevalence of MTHFR 677T allele and Covid-19 incidence and mortality worldwide. 
There is a clear trend towards the worldwide prevalence of MTHFR 677T allele and COVID-19 incidence and mortality. The prevalence of MTHFR 677T allele in the Latino population and the incidence and mortality for Covid-19 was higher for this ethnic group than that reported for most other populations globally. Statistical analysis showed a relatively strong correlation between 677T allele and death from coronavirus. 
Genetic polymorphism of MTHFR C677T may modulate the incidence and severity of Covid-19 pandemic infection. 
Keywords: Homocysteine � MTHFR gene � MTHFR 677T mutation prevalence � MTHFR C677T polymorphism � Covid-19 vulnerability
*Address for Correspondence: Ponti G, Division of Clinical Pathology, Department of Surgical, Medical, Dental and Morphological Sciences with Interest in Transplant, Oncological and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy, E-mail: giovanni.ponti@unimore.it
Copyright: � 2021 Ponti G, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 11 December, 2020; Accepted: 21 January, 2021; Published: 28 January, 2021
Introduction
Since the beginning of the novel coronavirus pandemic, caused by the viral pathogen Covid-19, the medical and scientific community is facing challenges for managing patients and identifying reliable biomarkers related to disease progression, in order to promptly stratify patients for their risk of critical manifestations. Trustworthy biomarkers would be helpful for screening, clinical management, and prevention of serious complications. In the absence of specific treatment and vaccine for the Covid-19, there is an urgent need to find markers that predict severe outcomes for patients with a confirmed or suspected Covid-19 diagnosis. It is crucial to identify clinical, epidemiological and laboratory markers for one of the main causes of mortality, especially regarding the damage to microvasculature which can potentially be modifiable by safe therapeutic interventions.
At present, there are over 25 million confirmed Covid-19 cases with 900 thousand deaths. Looking the worldwide epidemiologic data, there are remarkable differences among countries regarding Covid-19 infection rates and mortality, especially comparing very high data relative to United States of America or South America and sub-Saharan Africa or Finland, where incidence and mortality appear remarkably low (WHO Coronavirus Disease (COVID-19) Dashboard https://covid19.who.int/). This simple epidemiological observation represents the base for searching genetic differences among populations or ethnicities which may explain different clinical manifestations of COVID-19 infection [1,2].  
In addition to serological and clinical biomarkers that are clearly correlated with a severe clinical course of Covid-19 infection [3,4] the role of Homocysteine (Hcy) as an important prognostic marker has been recently hypothesized [4,5]. The role of Hcy in several metabolic and inflammatory processes has already been demonstrated, and different populations with different ethnical predominances show different prevalences for MTHFR gene mutations and MTHFR activities [6]. The population frequency of 677T allele homozygosity ranges from 1% or less among Blacks from Africa and the Finnish population to 20% or more among Latino and US Hispanics. Intriguingly, the world distribution of MTHFR C677T polymorphism has a high degree of heterogeneity following a  geographical gradient of south-north and west-east both in Europe and Americas [7-9]. 
Homocysteine has been under a lot of speculation since its discovery in 1932 [10]. It is known that a high plasma level of homocysteine significantly increases the incidence of vascular damage in both small and large vessels [10,11]. Hyperhomocysteinemia has neurotoxic, neuroinflammatory, neurodegenerative, proatherogenic, prothrombotic and prooxidative effects [12]. Homocysteine concentrations above the 90th percentile are associated with increased risk of degenerative and atherosclerotic processes [13] in the coronary, cerebral and peripheral circulatory system. In this regard, determining homocysteine together with other cardiovascular risk markers (Apo B, Lp (a), LDL, fibrinogen, PAI-1) now is implemented in the clinical practice [14]; moreover, recent evidence suggests the role of homocysteine as a risk factor for thromboembolism, given its effect on platelet reactivity [15]. 
Homocysteine has been found to be a predictor of disease progression in 273 patients with mild Covid-19 disease in Shanghai: 72 of the patients showed disease progression as assessed by lung CT scan. More than 40 parameters were measured in these 273 patients at admission of which only age, homocysteine and monocyte-to-lymphocyte ratio (MLR) were found as significant predictors of disease progression as shown by CT changes in the lung. Patients with hyperhomocysteinemia (>15.4 �mol/L) had a three-fold increased risk of CT changes progression. Of the three predictor markers, only homocysteine is readily modifiable. Very recent data witnessed a predictive value of Hcy (together with age, MLR, and period from disease onset to hospital admission) for severe pneumonia on chest CT at first week from Covid-19 patients, but did not report additional organ involvement [5].
It is known that homocysteine is an efficacious biomarker of cardiovascular risk, even though cardiovascular complications are critical in hospitalized Covid-19 patients Hcy has not yet been adopted to be used for the stratification of Covid-19 patients and it has not been included in prospective studies focused on laboratory markers useful for the clinical evaluation of the Covid-19 patients. To our knowledge, till today, no evidences have been published about the MTHFR gene polymorphisms that are clearly implicated into a defective Hcy metabolism and Covid-19 disease. The purpose of our research was to illustrate the relationship between the prevalence of the genetic polymorphisms of MTHFR C677T and COVID-19 incidence and mortality rates, demonstrating that COVID-19 incidence and mortality rates are strongly correlated to the prevalence of MTHFR 677C>T mutation which is linked explicitly to pro-thrombotic events due to altered homocysteine metabolism.  
Materials and Methods
Data regarding MTHFR status, regarding MTHFR 677C>T gene mutation, were obtained from the interrogation of the Genome Aggregation Database (genomAD) which is publicly available from the web�https://gnomad.broadinstitute.org.� Covid-19 cases, including prevalence and mortality, were obtained from�https://www.worldometers.info/coronavirus� 27th August 2020. 
MedCalc Statistical Software version 14.8.1 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2014) was used to perform statistical analysis. Correlation analysis was used to determine whether the values of two variables are associated. The correlation expresses the degree that, on an average, two variables change correspondingly. If one variable increases when the second one increases, then there is a positive correlation. In this case, the correlation coefficient will be closer to 1. 
The P-value is the probability that the current result to be found if the correlation coefficient were, in fact zero (null hypothesis). If this probability is lower than the conventional 5% (P <0.05) the correlation coefficient is called statistically significant.
Correlations between the measured variables in each group were analyzed using Pearson�s correlation method. All statistical tests were performed at a significance level (�) of 0.05.
Results
The analysis examined their associations for the allele frequency with cases of coronavirus COVID-19 death and incidence for the polymorphisms. Subgroup analyses were stratified by ethnicity (Table 1). Officially reported Covid-19 cases and the number of Covid-19 related deaths were stratified according to the ethnic groups as well (Table 1).
A correlation between MTHFR 677T allele prevalence and Covid-19 incidence and mortality rates can be clearly observed if data were stratified for different ethnic groups, demonstrating the presence of a gradient with South-North and East-West directions worldwide. The frequency of MTHFR 677T allele in the Latino population (50%) was higher than that reported for most of the other populations in the world, similarly coronavirus death correlation with the frequency of this allele in most of the other populations was lower (Finnish, African sub-Saharan, etc.) (Figure 1, 2). Correlation analysis showed a relatively strong correlation between 677T allele and death coronavirus with 85%, p=0.03.
The correlation between the allele frequency and coronavirus mortality was found very high (85%) (Figure 3,4).
Discussion
The relationship between the prevalence of the genetic polymorphisms of MTHFR C677T and COVID-19 incidence and mortality rates seems to be intriguing. It may be a useful biomarker to stratify COVID-19 infection severity and can be used for preventive medical treatments and supplementations. 
The correlation between Hcy level and COVID-19 severity of infection has been recently demonstrated, [4,5] currently under our evaluation in a cohort of 313 patients affected by COVID-19 infection which confirms the significant correlation between blood Hcy > 16 �mol/L and severe prognosis or mortality.
Several studies have clarified the pathogenic correlation between COVID-19 infection and Hcy metabolism. Recently, it has been described the novel regulatory mechanisms directly involved with Hcy that activates the angiotensin II type receptor [16,17]. Ferroptosis, a newly identified form of regulated cell death, is characterized by iron and lipid reactive oxygen species (ROS) accumulation and smaller mitochondria with condensed mitochondrial membrane densities. Still, it does not share morphological, biochemical, or genetic similarities with other forms of regulated cell death, such as apoptosis [18]. Increasing evidence suggests that ferroptosis dysfunction is positively related to various human diseases, including tumorigenesis [19]. Ferroptosis was found to be linked to neurological disturbances, including cognitive impairment [20], ageusia, and anosmia (taste and smell loss) [21,22] that are common manifestations of Covid-19 disease.
The SARS-CoV-2 may involve the transfer of methyl group for viral RNA capping from the host cell synthesized S-adenosylmethionine (SAM). The latter is converted into S-adenosylhomocysteine (SAH), which further in the presence of SAH hydrolase (SAHH) removes adenosine, and produces an intermediate product called �homocysteine,� which is recycled by remethylation and trans-sulphuration pathway in the human body [23].
Regarding the genetic background of Hcy metabolisms, the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is involved in the folate metabolism. The MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate which produces methyl donor for the conversion of homocysteine to methionine [24].
The MTHFR gene is located on chromosome 1 (1p36.3), and two common alleles, the 677T (thermolabile) allele and the A1298C allele, have been described. The population frequency of 677T homozygosity ranges from 1% or less among Blacks from Africa and the United States to 20% or more among Italians and US Hispanics. 677T homozygosity in infants is associated with a moderately increased risk for spina bifida (pooled odds ratio = 1.8; 95% confidence interval: 1.4, 2.2). 
The 677T allele is characterized by a point mutation at position 677 of the MTHFR gene that converts a cytosine (C) into a thymine (T); this mutation results in an amino acid substitution (alanine to valine) in the enzyme. The 677T allele homozygous mutated subjects have higher increased blood homocysteine levels while the heterozygous mutated subjects have mildly raised homocysteine levels compared with the normal, non-mutated controls [6].
The population frequency of the 677T allele showed regional and ethnic variations (Table 1). For example, the allele frequency was high in Italy and among Hispanics living in California and was low among US Blacks and in some areas of sub-Saharan Africa. The frequency of 677T homozygosity showed similar variability [25]. Amongst the European, the homozygous allele was found highest in the Italians and lowest in the Germans [26-28]. The prevalence of the homozygous TT genotype was 10-12% in Europe's several areas (for example, Spain, France, and Hungary). In Britain, the percentage of homozygosity in the population was approximately 13%. However, the prevalence appeared to be lower (4% and 6%, respectively) in Finland, Helsinki, and the northern Netherlands. In contrast, in some southern European areas, it was much higher (26% and 20% in Campania and Sicily, respectively). In the Americas, the frequency of the homozygous TT genotype was more elevated in Mexico (32%), intermediate in Atlanta (11% among whites), and somewhat lower in Alberta (6%). For the Blacks living in America and Brazil, the frequency of homozygosity was very low (1 or 2% only) [29-31].
In Australia, TT prevalence was 7.5% among whites. Among the Whites not within Europe, the homozygous mutation percentages ranged from 10 to 14% in countries like Canada, America, Brazil, and Australia [32-34]. Zero rate was found on the homozygosity of the sub-Saharan African population.
The several fold variations in the prevalence of the TT homozygous genotype across the study areas were also consistent, in some areas, with the presence of geographical gradients. In Europe, for example, the prevalence of the TT genotype increased in a roughly southerly direction, from low values in the north (4-7% in Finland, Helsinki, northern Netherlands, and Russia), to intermediate values (8-10%) in France and Hungary, to higher values in southern Europe (12-15% in Spain and northern Italy), peaking in south Italy (20-26% in Campania and Sicily). In North America, TT homozygotes' frequency increased from western Canada (Alberta) to the southeastern United States (Atlanta) and peaked in Mexico [7].
The comparison of the prevalence of the homozygousity for MTHFR 677T mutated allele and the incidence and mortality by Covid-19 showed a high degree of correlation, especially regarding South-North and East-West gradients, as well as for Americans, Europeans, and Asians populations. This data could be traced back to ancestral migratory phenomena related to population genetic or to a reduced dietary intake of B9 (folic acid) and other B-vitamins that could characterize different dietary regimens among different cultures [35]. 
The genetic data related to MTHFR status coupled with Hcy dosage could represent important information for the assessment and stratification of Covid-19 patients. In association with other epidemiologic, hematologic, biochemical and functional parameters, these data could be useful to define better population-based risk strategies to fight Covid-19 infection and lethality. It has been demonstrated that the presence of MTHFR 677T may result in the need for a higher folate and B-vitamins intake to maintain normal Hcy levels; therefore, a preventive therapeutic integration of Folic acid and B-vitamins could result in the reduction of prevalence and mortality for Covid-19 viral infection [35-39]. 
Conclusion
In conclusion, Genetic polymorphism of MTHFR 677T may modulate the risk of Covid-19 incidence and severity. 
Population data on correlation between the 677T allele and Covid-19 incidence and mortality would be very useful in regional and national management strategy and might help the population and public health geneticists to assess the potential impact of preventive measures based on environmental modifications. Some adverse biochemical effects of the thermolabile enzyme coded by the T allele, such as the increase in total plasma homocysteine, appear to be reversible by increasing the consumption of the vitamin B and folic acid.
Acknowledgments
GP and LP designed the study and collected data from recruited cases. SK analyzed data and performed the statistics. MM, NL, AT, GO, RI and TO analysed and wrote the Results and Discussion section including the literature review, prepared the manuscript, translated it and managed all the correspondence for publishing. All authors read and approved the final manuscript.
References
1. Caspar I Van Der Made, Annet Simons, Janneke Schuurs-Hoeijmakers and Guus Van Den Heuvel, et al. �Presence of genetic variants among young men with severe COVID-19.� J Am Med Assoc 7 (2020): 663-673.
2. Krystal J Godri Pollitt, Jordan Peccia, Albert I Ko and Naftali Kaminski, et al. �COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission.� Hum Genomics 14 (2020): 1-7.
3 Giovanni Ponti, Monia Maccaferri, Cristel Ruinia and Aldo Tomasi, et al. �Biomarkers associated with COVID-19 disease progression.� Crit Rev Clin Lab Sci 6 (2020): 389-399.
4. Giovanni Ponti, Cristel Ruini, and Aldo Tomasi. "Homocysteine as a potential biomarker of cardiovascular risk in patients with COVID-19." Med Hypotheses 143 (2020): 111-112.
5. Zongguo Yang, Jia Shi, Zhang He and Ying L�, et al. �Predictors for imaging progression on chest CT from coronavirus disease 2019 (COVID-19) patients.� Aging 12 (2020): 6037.
6. Siaw-Cheok Liew and Esha Das Gupta. �Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases.� Eur J Med Genet 58 (2015): 1-10.
7. Bridget Wilcken, Fedric Bamforth, Zu Li and Harry Zhu, et al. �Geographical and ethnic variation of the 677C> T allele of 5, 10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas worldwide.� J Med Genet 40 (2003): 619-625.
8. Wang Yafei, Pei Lijun, Wang Jinfeng and Zheng Xiaoying. �Is the prevalence of MTHFR C677T polymorphism associated with ultraviolet radiation in Eurasia?.� J Hum Genet 57 (2012): 780-786.
9. Upendra Yadav, Pradeep Kumar, Sanjay Gupta and Vandana Rai. �Distribution of MTHFR C677T gene polymorphism in healthy North Indian population and an updated meta-analysis.� Indian J Clin Biochem 32 (2017): 399-410.
10. Lewis W Butz, and Vincent du Vigneaud. �The formation of a homologue of cystine by the decomposition of methionine with sulfuric acid.� J Biol Chem 99 (1932): 135-142.
11. Brittany Balint, Viola Kosgei Jepchumba, Jean-Louis Gu�ant and Rosa-Maria Gu�ant-Rodriguez. "Mechanisms of homocysteine-induced damage to the endothelial, medial and adventitial layers of the arterial wall." Biochimie 173 (2020): 100-106.
12. Stefano Zoccolella, Davide Martino, Giovanni Defazio and Paolo Lamberti, et al. "Hyperhomocysteinemia in movement disorders: current evidence and hypotheses." Curr Vasc Pharmacol 4 (2006): 237-243.
13. Ian M. Graham. �Plasma Homocysteine as a Risk Factor for Vascular Disease.� J Am Med Assoc 277 (1997): 1775-1781.
14. Philippe Durand, Michel Prost, Nadine Loreaua and Suzanne Lussier-Cacan, et al. "Impaired homocysteine metabolism and atherothrombotic disease." Lab Invest 81 (2001): 645-672.
15. Zhou-Qing Kang, Ying Yang and Bo Xiao. "Dietary saturated fat intake and risk of stroke: Systematic review and dose�response meta-analysis of prospective cohort studies." Nutr Metab Cardiovasc Dis 30 (2020): 179-189.
16. Ji Cao, Xiaobing Chen, Li Jiang and Bin Lu, et al. "DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase." Nat Commun 11 (2020): 1-15.
17. Lingyu Lv, Wei Ji, Rui Yin and Shicheng Zhang, et al. "Design of full-bandwidth ROADM based on MMI and MRRs." Opt Quantum Electron 50 (2018): 1-11.
18. Scott J Dixon, Kathryn M Lemberg, Michael R Lamprechta and Rachid Skouta, et al. "Ferroptosis: an iron-dependent form of nonapoptotic cell death." Cell 149 (2012): 1060-1072.
19. Bin Lu, Xiao Bing Chen, Mei Dan Yinga and Qiao Jun He, et al. "The role of ferroptosis in cancer development and treatment response." Front Pharmacol 8 (2018): 992.
20. Yiran Sun, Libo He, Taoyu Wanga and Wan Hua, et al. "Activation of p62-keap1-Nrf2 pathway protects 6-hydroxydopamine-induced ferroptosis in dopaminergic cells." Mol Neurobiol 57 (2020): 4628-4641.
21. Tokio Osaki, Masashi Ohshima, Yukinobu Tomitaa and Noriko Matsugi, et al. "Clinical and physiological investigations in patients with taste abnormality." J Oral Maxillofac Pathol 25 (1996): 38-43.
22. Mehmet Emre Dinc, Abdullah Dalgic, Seckin Ulusoy and Denizhan Dizdar et al. "Does iron deficiency anemia affect olfactory function?." Acta Otolaryngol 136 (2016): 754-757.
23. Yogendra Singh, Gaurav Gupta, Saurabh Satija and Poonam Negi, et al. "RAAS blockers in hypertension posing a higher risk towards the COVID 19." Dermatol Ther 10 (2020): 13501.
24. Philippe Goyette, David S Rosenblatt and Rima Rozen. "Homocystinuria (methylenetetrahydrofolate reductase deficiency) and mutation of factor V gene." J Inherit Metab Dis 21 (1998): 690-691.
25. Lorenzo D Botto and Quanhe Yang. "5, 10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review." Am J Epidemiol 151 (2000): 862-877.
26. Mathew Adams, Peter D. Smith, Daniel Martin and Joel R Thompson, et al. "Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction." QJM 89 (1996): 437-444.
27. Derrick John Bowen, Sany Bowley, Marwel John and Peter William Collins. "Factor V Leiden (G1691A), the Prothrombin 3�-Untranslated Region Variant (G20210A) and Thermolabile Methylenetetrahydrofolate Reductase (C677T): A Single Genetic Test Genotypes all Three Loci�Determination of Frequencies in the S. Wales Population of the UK." Thromb Haemost 79 (1998): 949-954.
28. Hugh S Markus, Nadira Ali, Ravi Swaminathan and Adi Sankaralingam, et al. "A common polymorphism in the methylenetetrahydrofolate reductase gene, homocysteine, and ischemic cerebrovascular disease." Stroke 28 (1997): 1739-1743.
29. Valder R Arruda, Lucia H. Siqueira, Marilda S. Gon�alves and Paula M. von Zuben, et al. "Prevalence of the mutation C677�! T in the methylene tetrahydrofolate reductase gene among distinct ethnic groups in Brazil." Am J Med Genet 78 (1998): 332-335.
30. Anne Dilley, Harland Austin, Wang Craig Hooper and Cathy Lally, et al. "Relation of three genetic traits to venous thrombosis in an African-American population." Am J Epidemiol 147 (1998): 30-35.
31. Roger E Stevenson, Charles E. Schwartz, Yan Z. Du and Myron J. Adams Jr. "Differences in methylenetetrahydrofolate reductase genotype frequencies, between Whites and Blacks." Am J Hum Genet 60 (1997): 229.
32. Jia Chen, Edward Giovannucci, Karl Kelsey and Eric B. Rimm, et al. "A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer." Cancer Res 56 (1996): 4862-4864.
33. Jing Ma, Meir J. Stampfer, Charles H. Hennekensa and Phyllis Frosst, et al. "Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians." Circulation 94 (1996): 2410-2416.
34. David EL Wilcken, Xing L. Wang, Ah Siew Sim and Rubil Michael McCredie. "Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation." Arterioscler Thromb Vasc Biol 16 (1996): 878-882.
35. Omer C Ibrahimagic, Dzevdet Smajlovic, Zikrija Dostovica and Zejneba Pasic, et al. "Hyperhomocysteinemia and its treatment in patients with parkinson�s disease." Mater Sociomed 28 (2016): 303.
36. Rozen, Rima. "Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR)." Thromb Haemost 78 (1997): 523-526.
37. Guglielmina Pepe, Olga Camacho Vanegas, Betti Giusti and Tamara Brunelli, et al. �Heterogeneity in world distribution of the thermolabile C677T mutation in 5, 10-methylenetetrahydrofolate reductase.� Am J Hum Genet 63 (1998): 917-920.
38. Min Shi, Diana Caprau, Paul Romittia and Kaare Christensen, et al. "Genotype frequencies and linkage disequilibrium in the CEPH human diversity panel for variants in folate pathway genes MTHFR, MTHFD, MTRR, RFC1, and GCP2." Birth Defects Res A Clin Mol Teratol 6+,8KLTUWX]^�DZ�iS:S:$+h�|SB*CJOJQJ^JaJmH	@phsH	@1h5S�h@@B*CJOJQJ^JaJmH	@phsH	@+hn/�B*CJOJQJ^JaJmH	@phsH	@+hbrB*CJOJQJ^JaJmH	@phsH	@1h5S�h�2�B*CJOJQJ^JaJmH	@phsH	@1h�V&h�V&B*CJOJQJ^JaJmH	@phsH	@+h];�B*CJOJQJ^JaJmH	@phsH	@7h5S�h�2�5�B*CJOJQJ\�^JaJmH	@phI&msH	@7h�V&h�V&5�B*CJOJQJ\�^JaJmH	@phI&msH	@,L`�~	�	*
l
�
h���u�����������������$d��xa$gd�\k$��d���7$8$H$]�^�a$gd��dhgd8q
��d���7$8$H$]�^�$
����d���7$8$H$]�^�a$gd�H�$��d���7$8$H$]�^�a$^_`����������				#	$	6	7	H	I	Z	[	n	o	|	}	~	��������n�n�n�n�n�n�n�n�nV/h�h�2�5�B*OJQJ\�^JmH	@phsH	@'hn/�hn/�5�B*H*OJPJQJph�hn/�hn/�5�OJPJQJ4hO!�h�2�5�B*CJ OJQJ^JaJ mH	@phsH	@ hn/�5�CJ OJPJQJ\�aJ &hn/�hn/�5�CJ OJPJQJ\�aJ 1h5S�h�2�B*CJOJQJ^JaJmH	@phsH	@+h�H�B*CJOJQJ^JaJmH	@phsH	@~		�	�	*
+
l
m
�
�
hi������


W
\
������������������ç�}k}k}k}k}Z h�G�h�G�CJOJPJQJaJ#h�\kh�\k6�CJOJPJQJaJ h�\kh�\kCJOJPJQJaJ1h��5�B*CJOJQJ\�^JaJmH	@phsH	@7h5S�h��5�B*CJOJQJ\�^JaJmH	@phsH	@hT&�hT&�6�OJQJ#h8q
h8q
6�B*H*OJQJph�h8q
h8q
6�OJQJ#hT&�hB6�B*H*OJQJph������
&'().����҅���t[E*4h�\kh�\k6�B*CJOJQJ^JaJmH	@phsH	@+h�PB*CJOJQJ^JaJmH	@phsH	@1h��h�PB*CJOJQJ^JaJmH	@phsH	@ hT&�hT&�CJOJPJQJaJ hp�hp�CJOJPJQJaJ#h�\kh�\k6�CJOJPJQJaJ1h��h��B*CJOJQJ^JaJmH	@phsH	@ h�Ph�PCJOJPJQJaJ h�\kh�\kCJOJPJQJaJ7h5S�h��5�B*CJOJQJ\�^JaJmH	@phsH	@.ABCDZ[x}��]�ռ��q_P@3'h�|Sh�|S6�OJQJh~6�CJOJQJaJhtA�h�#�6�CJOJQJaJh�|S6�CJOJPJQJaJ#h�|Sh�|S6�CJOJPJQJaJ=h5S�h@@5�6�B*CJOJQJ\�]�^JaJmH	@phsH	@+h��B*CJOJQJ^JaJmH	@phsH	@+h�PB*CJOJQJ^JaJmH	@phsH	@1h��h�PB*CJOJQJ^JaJmH	@phsH	@ hp�h�PCJOJPJQJaJ1h�\kh�\kB*CJOJQJ^JaJmH	@phsH	@�[����`e�Q"&1&�'�)�*,(,�����������������$d��xa$gdW+�$d��xa$gd�|$d��xa$gd�K~$d��xa$gd
$��d���7$8$H$]�^�a$$��d���7$8$H$]�^�a$gdzrW]_g������������ͱ�v]vA(v�1h�8�6�B*CJOJQJ]�^JaJmH	@phsH	@7h�|Sh�|S6�B*CJOJQJ]�^JaJmH	@phsH	@1h�|S6�B*CJOJQJ]�^JaJmH	@phsH	@7h5S�h@@6�B*CJOJQJ]�^JaJmH	@phsH	@=h5S�h@@5�6�B*CJOJQJ\�]�^JaJmH	@phsH	@7h5S�h�2�6�B*CJOJQJ]�^JaJmH	@phsH	@#hM#hM#6�CJOJPJQJaJhtA�h�#�6�CJOJQJaJhtA�h��6�CJOJQJaJ��������������������˳˝�n�V˳˝@n��@+h�aB*CJOJQJ^JaJmH	@phsH	@.h�G�B*CJOJQJ\�^JaJmH	@phsH	@1h5S�h@@B*CJOJQJ^JaJmH	@phsH	@+hT&�B*CJOJQJ^JaJmH	@phsH	@+h�r�B*CJOJQJ^JaJmH	@phsH	@.h~B*CJOJQJ\�^JaJmH	@phsH	@.h�aB*CJOJQJ\�^JaJmH	@phsH	@7h5S�h@@5�B*CJOJQJ\�^JaJmH	@phsH	@����	�����������]b��FM���^bMQ��� � L"O"�ʮ�������v�v���v���������_����������,h
h
B*CJH*OJPJQJaJph�#h
h
6�CJOJPJQJaJ)h
h
B*CJOJPJQJaJph� h
h
CJOJPJQJaJ7h5S�h�2�5�B*CJOJQJ\�^JaJmH	@phI&msH	@7h5S�h@@5�B*CJOJQJ\�^JaJmH	@phI&msH	@1h5S�h�2�B*CJOJQJ^JaJmH	@phsH	@%O"'$,$%
%�%�%�%&&0&1&@&E&X&]&�'�',,,�������Ͼ��xfxfxOx:x)h�_�h�|B*CJOJPJQJaJph�,h�|h�|B*CJH*OJPJQJaJph�#h�|h�|6�CJOJPJQJaJ h�|h�|CJOJPJQJaJ1h�V�5�B*CJOJQJ\�^JaJmH	@phI&msH	@7h�gh�g5�B*CJOJQJ\�^JaJmH	@phI&msH	@ h�g�h�g�CJOJPJQJaJh
CJOJPJQJaJ#h
h
6�CJOJPJQJaJ h
h
CJOJPJQJaJ,,&,(,�-�-b.k.�.�.�/�/�0�0�1�1�1�1�1�1�Ӻ�������������qUD h�pzh�pzCJOJPJQJaJ7h�8�h�8�5�B*CJOJQJ\�^JaJmH	@phI&msH	@ h�Q�h�Q�CJOJPJQJaJ#h`w/h(P�6�CJOJPJQJaJ)h(P�h(P�B*CJOJPJQJaJph� h(P�h(P�CJOJPJQJaJ1h<�5�B*CJOJQJ\�^JaJmH	@phI&msH	@7h�VXh�VX5�B*CJOJQJ\�^JaJmH	@phI&msH	@ hnV0hnV0CJOJPJQJaJ(,m.'1�1�1�2�3�7S9�:b< >�B�C�F�HsK~K�K�MN��������������������$d��xa$gd�Sgd�pz$d��xa$gdXKg$d��xa$gd�pz$dh7$8$H$a$gd�8�$d��xa$gd(P��1�1+303�3�3�4�4S6W6�6�6B7F7t7{7N8m8M9Q9�9�9�9�9�:�:�:�:�<�<>>]?a?�?�?�?�B�BC�C�F�F�F�F�H�H�H�HZJ_JRKiKpKqKrK���������������ܹ����������������ܧ���������������ܹǹ� h�8�h�8�CJOJPJQJaJ#h�pzB*CJOJPJQJaJph�h�pzCJOJPJQJaJ)h�pzh�pzB*CJOJPJQJaJph� h�pzh�pzCJOJPJQJaJ#h�pzh�pz6�CJOJPJQJaJ7rKsK~K�K�K�M�M
NN�O�O�O��ųť�p_Q57h5S�h@@5�B*CJOJQJ\�^JaJmH	@phI&msH	@h��CJOJPJQJaJ h�0h�0CJOJPJQJaJ1h�S5�B*CJOJQJ\�^JaJmH	@phI&msH	@7h�Sh�S5�B*CJOJQJ\�^JaJmH	@phI&msH	@h�VXCJOJPJQJaJ#h�pzh�pz6�CJOJPJQJaJ h�pzh�pzCJOJPJQJaJ1h�}5�B*CJOJQJ\�^JaJmH	@phI&msH	@ h*;Nh�8�CJOJPJQJaJN�O�OXP-Q�Q�R?S�S
U�U�V����rrrrrrr9$d���$d����%d����&d����'d����(d����N���������O���������P���������Q���������R���������a$gdwt�9$d���$d����%d����&d����'d����(d����N���������O���������P���������Q���������R���������a$gd�k�$��d���7$8$H$]�^�a$gd�%�O�O�O�O�O�O�O�O�O3P6P8PDPEPVPWPXP[PePtP�P�P�P��������l���ZH�����#hwt�B*CJOJPJQJaJph#h�k�B*CJOJPJQJaJph&h�06�B*CJOJPJQJaJph,h3�h�Z
6�B*CJOJPJQJaJph#h�Z
B*CJOJPJQJaJph)h�0h�0B*CJOJPJQJaJph#h�0B*CJOJPJQJaJph)h�Bh�EUB*CJOJPJQJaJph4h�Bh�2�B*CJOJQJ\�^JaJmH	@phsH	@�P�P�P
QQQQQQ+Q,Q.Q/Q8QLQoQvQyQ�Q���د���Ø�mXmF1X)hwt�hwt�B*CJOJPJQJaJph#h� �B*CJOJPJQJaJph)ht]ht]B*CJOJPJQJaJph#ht]B*CJOJPJQJaJphh� �h� �#hwt�B*CJOJPJQJaJph,h�0h�06�B*CJOJPJQJaJph&h�06�B*CJOJPJQJaJph)h�0h�0B*CJOJPJQJaJph#h3�B*CJOJPJQJaJph)h3�h3�B*CJOJPJQJaJph�Q�Q�Q�Q�Q�Q�Q�Q�QhRiRlRwR�����saL�8!,h�V�h�V�6�B*CJOJPJQJaJph&h�V�6�B*CJOJPJQJaJph)h�V�h�V�B*CJOJPJQJaJph#h�V�B*CJOJPJQJaJph#hwt�B*CJOJPJQJaJph)h� �h� �B*CJOJPJQJaJph)ht]ht]B*CJOJPJQJaJph#h� �B*CJOJPJQJaJph,ht]ht]6�B*CJOJPJQJaJph)hwt�hwt�B*CJOJPJQJaJph#ht]B*CJOJPJQJaJphwRxRyR{R|R}RR�R�R�R�R�R�R�R�R�R�R�R�R�R�R&S(S-S.S�����������ر��x�x��x�aJ,h�Ph�P6�B*CJOJPJQJaJph,hDKkhDKk6�B*CJOJPJQJaJph)hDKkhDKkB*CJOJPJQJaJph#hDKkB*CJOJPJQJaJph#hwt�B*CJOJPJQJaJph)hwt�hwt�B*CJOJPJQJaJph#h�V�B*CJOJPJQJaJph)h� �h� �B*CJOJPJQJaJph#h� �B*CJOJPJQJaJph.S/S0S1S2S4S6S9S=S?SBSMSQSdSgS�S�S�S�S�S�S�S�S�S�S�S�ST������걜�xcx�c�L�x�x��xƜ�,h�h�6�B*CJOJPJQJaJph)h�h�B*CJOJPJQJaJph#h�B*CJOJPJQJaJph#hwt�B*CJOJPJQJaJph)hwt�hwt�B*CJOJPJQJaJph)hDKkhDKkB*CJOJPJQJaJph#h�PB*CJOJPJQJaJph#hDKkB*CJOJPJQJaJph)h�Ph�PB*CJOJPJQJaJphTTTTT"T$T)T.T7T>TAT�T�T�T�T�T�T�T�T�TUU
U
UU������ññ�꜅nñձ���\J#h96B*CJOJPJQJaJph#hwt�B*CJOJPJQJaJph,h:#�h:#�6�B*CJOJPJQJaJph,h�zKh�zK6�B*CJOJPJQJaJph)hwt�hwt�B*CJOJPJQJaJph#h:#�B*CJOJPJQJaJph#h�zKB*CJOJPJQJaJph)h:#�h:#�B*CJOJPJQJaJph)h�zKh�zKB*CJOJPJQJaJphUU0UCUFU�U�U�U�U�U�U�U�U�U�U�U�U�U�U�UVVuVxV�V�V�V�����ï��؆q�q��_�����ØH�,hm�hm�6�B*CJOJPJQJaJph#hwt�B*CJOJPJQJaJph)hsj�hsj�B*CJOJPJQJaJph#hsj�B*CJOJPJQJaJph,h96h966�B*CJOJPJQJaJph&h966�B*CJOJPJQJaJph)hwt�hwt�B*CJOJPJQJaJph#h96B*CJOJPJQJaJph)h96h96B*CJOJPJQJaJph�V�V�V�V�V�V�V�V�V�V+W.W9W��î��u`K`K4,h96h��6�B*CJOJPJQJaJph)h��h��B*CJOJPJQJaJph)h96h��B*CJOJPJQJaJph#h��B*CJOJPJQJaJph#h��B*CJOJPJQJaJph)h�Bhwt�B*CJOJPJQJaJph)hwt�hwt�B*CJOJPJQJaJph)h96h96B*CJOJPJQJaJph)hm�hm�B*CJOJPJQJaJph#hm�B*CJOJPJQJaJph9W:WEWLWMWNWRW"X+X@XAXEXLXyX}X�X�X�X��Ű��t]t��K6K6K6)hG<hG<B*CJOJPJQJaJph#hG<B*CJOJPJQJaJph,h��h��6�B*CJOJPJQJaJph)h��h��B*CJOJPJQJaJph#h��B*CJOJPJQJaJph)h��h��B*CJOJPJQJaJph)h��h��B*CJOJPJQJaJph)h96h��B*CJOJPJQJaJph#h��B*CJOJPJQJaJph&h��6�B*CJOJPJQJaJph�VNWAXY�Y5Z[�[a\]�]�^O_�_faub!c����������������9$d���$d����%d����&d����'d����(d����N���������O���������P���������Q���������R���������a$gd��9$d���$d����%d����&d����'d����(d����N���������O���������P���������Q���������R���������a$gd���X�X
YYYYYXY[Y]YjYvYY�Y�Y�Y�Y��°����r^����L:#h�-�B*CJOJPJQJaJph#h�lKB*CJOJPJQJaJph&h�W�6�B*CJOJPJQJaJph,h3�h�W�6�B*CJOJPJQJaJph#h�W�B*CJOJPJQJaJph)h�W�h�W�B*CJOJPJQJaJph#hG<B*CJOJPJQJaJph#h��B*CJOJPJQJaJph)hG<hG<B*CJOJPJQJaJph,hG<hG<6�B*CJOJPJQJaJph�Y�Y�Y�Y�YZ Z4Z5Z9ZBZIZRZ�Z�Z[[[[[[�����ꯝ�v�v_v�MF4M#h 
#B*CJOJPJQJaJphh 
#h 
##hF
B*CJOJPJQJaJph,h�M h�M 6�B*CJOJPJQJaJph)h�M h�M B*CJOJPJQJaJph#h�M B*CJOJPJQJaJph#h�s�B*CJOJPJQJaJph#h�W�B*CJOJPJQJaJph,h�-�h�-�6�B*CJOJPJQJaJph#h�-�B*CJOJPJQJaJph)h�-�h�-�B*CJOJPJQJaJph[5[9[B[G[�[�[�[�[�[�[�[�[�[\;\O\`\a\e\l\�����ꯝ�v�v�v_v�M;#h��B*CJOJPJQJaJph#hpUrB*CJOJPJQJaJph,h9|Ih9|I6�B*CJOJPJQJaJph)h9|Ih9|IB*CJOJPJQJaJph#h9|IB*CJOJPJQJaJph#h$B*CJOJPJQJaJph#hF
B*CJOJPJQJaJph,h 
#h 
#6�B*CJOJPJQJaJph#h 
#B*CJOJPJQJaJph)h 
#h 
#B*CJOJPJQJaJphl\�\�\�\�\]]]2]A]O]T]�]�]�]�]�]�]�]�]b^���ꯝ�����q�؝_J_J)h��h��B*CJOJPJQJaJph#h��B*CJOJPJQJaJph,h�2�h�2�6�B*CJOJPJQJaJph)h�2�h�2�B*CJOJPJQJaJph#h�2�B*CJOJPJQJaJph#hpUrB*CJOJPJQJaJph,h��h��6�B*CJOJPJQJaJph#h��B*CJOJPJQJaJph)h��h��B*CJOJPJQJaJphb^o^�^�^�^�^�^�^�^�^$_<_N_O_S_^_~_�_�_�_�_��°������r��`N9N9N9)h*/h*/B*CJOJPJQJaJph#h*/B*CJOJPJQJaJph#h[�B*CJOJPJQJaJph,h+2h+26�B*CJOJPJQJaJph)h+2h+2B*CJOJPJQJaJph#h+2B*CJOJPJQJaJph#h�q�B*CJOJPJQJaJph#h�2�B*CJOJPJQJaJph)h��h��B*CJOJPJQJaJph,h��h��6�B*CJOJPJQJaJph�_�_�_�_``^`f`�`�`aa&a@aBaHaTabadafana�a��°������r�[�������F)h^b�h^b�B*CJOJPJQJaJph,hFBhFB6�B*CJOJPJQJaJph-hFBhFBB*CJOJPJQJ^JaJph)hFBhFBB*CJOJPJQJaJph#hFBB*CJOJPJQJaJph#hl�B*CJOJPJQJaJph#h[�B*CJOJPJQJaJph)h*/h*/B*CJOJPJQJaJph,h*/h*/6�B*CJOJPJQJaJph�a�aMb`btbubyb�b�b�b�bc c!c%clcmc�c��د��v�v_v��J8J#h[pB*CJOJPJQJaJph)h[ph[pB*CJOJPJQJaJph,h�}h�}6�B*CJOJPJQJaJph)h�}h�}B*CJOJPJQJaJph#h�}B*CJOJPJQJaJph#h!�B*CJOJPJQJaJph#hFBB*CJOJPJQJaJph,h^b�h^b�6�B*CJOJPJQJaJph)h^b�h^b�B*CJOJPJQJaJph#h^b�B*CJOJPJQJaJph�c�c�c�c�cdddd(dIeWekelepe�e�e�e�e�e�enf��°������r��`K9K9K9K#h��B*CJOJPJQJaJph)h��h��B*CJOJPJQJaJph#h�v�B*CJOJPJQJaJph,h�h�6�B*CJOJPJQJaJph)h�h�B*CJOJPJQJaJph#h�B*CJOJPJQJaJph#h[pB*CJOJPJQJaJph#h�}B*CJOJPJQJaJph)h[ph[pB*CJOJPJQJaJph,h[ph[p6�B*CJOJPJQJaJph!c�cle�fQhi�i�j�k�l[m�m�n������������������$��d���7$8$H$]�^�a$gdK9$d���$d����%d����&d����'d����(d����N���������O���������P���������Q���������R���������a$gd��nfzf�f�f�f�f g(gRg\g.h<hPhQhUhZhshvh�h�h�h�h�h��°������r��`N9N9N9N9)h�r�h�r�B*CJOJPJQJaJph#h�r�B*CJOJPJQJaJph#hiO�B*CJOJPJQJaJph,hiO�h/w�6�B*CJOJPJQJaJph)h/w�h/w�B*CJOJPJQJaJph#h/w�B*CJOJPJQJaJph#h|eB*CJOJPJQJaJph#h�v�B*CJOJPJQJaJph)h��h��B*CJOJPJQJaJph,h��h��6�B*CJOJPJQJaJph�hiiii$iFiNi�i�i�i�i�i�i�i�ij+j0j�j��°����r�`�K9K9K9K#hl	�B*CJOJPJQJaJph)hl	�hl	�B*CJOJPJQJaJph#h�r�B*CJOJPJQJaJph,ht+Aht+A6�B*CJOJPJQJaJph)ht+Aht+AB*CJOJPJQJaJph#ht+AB*CJOJPJQJaJph#h��B*CJOJPJQJaJph#hiO�B*CJOJPJQJaJph)h�r�h�r�B*CJOJPJQJaJph,h�r�h�r�6�B*CJOJPJQJaJph�j�j�j�j�j�j�j�j�j�j�k�k�k�k�k�k�k�k�kdl�l��°������r��`K`K`K4,h�h�6�B*CJOJPJQJaJph)h�h�B*CJOJPJQJaJph#h�B*CJOJPJQJaJph,h�8<h�8<6�B*CJOJPJQJaJph)h�8<h�8<B*CJOJPJQJaJph#h�8<B*CJOJPJQJaJph#ht+AB*CJOJPJQJaJph)hl	�hl	�B*CJOJPJQJaJph#hl	�B*CJOJPJQJaJph,hl	�hl	�6�B*CJOJPJQJaJph�l�l�l�l�l�l�l�l�l<mJmZm[m_m�m�m�m�mnPn��ƴ��������vaJa�v5)hY'�hY'�B*CJOJPJQJaJph,h.dMh.dM6�B*CJOJPJQJaJph)h.dMh.dMB*CJOJPJQJaJph#h.dMB*CJOJPJQJaJph,h�z�h�z�6�B*CJOJPJQJaJph)h�z�h�z�B*CJOJPJQJaJph#h�z�B*CJOJPJQJaJph#h�B*CJOJPJQJaJph#h�8<B*CJOJPJQJaJph)h�h�B*CJOJPJQJaJphPnRn�n�n�n�n�n�n�no+o0o�o�o�o����f�h����������د������q�o��]H]H]Ah�ph�p)h�ph�pB*CJOJPJQJaJph#h�pB*CJOJPJQJaJphU,hWThWT6�B*CJOJPJQJaJph)hWThWTB*CJOJPJQJaJph#hWTB*CJOJPJQJaJph#h.dMB*CJOJPJQJaJph,hY'�hY'�6�B*CJOJPJQJaJph)hY'�hY'�B*CJOJPJQJaJph#hY'�B*CJOJPJQJaJph7 (2003): 545-549.
39. Gaetano Gorgone, Vincenzo Belcastro, Laura Pierguidi and Anna Castrioto, et al. �Hyperhomocysteinemia recurrence in levodopa-treated Parkinson�s disease patients.� Eur J Neurol 17 (2010): 661-665.
How to cite this article: Giovanni Ponti, Lorenza Pastorino, Gabriella Oliva and Tomris Ozben, et al. �Covid-19 spreading across world correlates with 677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene prevalence.� J Mol Biomark Diagn 12 (2021): 447.
�����������!�@�A���髏sX@%4h��h��B*CJOJQJ\�^JaJmH	@phsH	@.h��B*CJOJQJ\�^JaJmH	@phsH	@4h��h��B*CJOJQJ\�^JaJmH	@phsH	@7h�Bh�S5�B*CJOJQJ\�^JaJmH	@phsH	@7h�Bh�Sc5�B*CJOJQJ\�^JaJmH	@phsH	@)h�phWTB*CJOJPJQJaJph)h�ph�pB*CJOJPJQJaJph&h�p6�B*CJOJPJQJaJph,h�ph�p6�B*CJOJPJQJaJph
A�C���������������ʯ�x�`�`�H0.h��B*CJOJQJ\�^JaJmH	@phsH	@.hIi�B*CJOJQJ\�^JaJmH	@phsH	@.h�lB*CJOJQJ\�^JaJmH	@phsH	@7h��h�Z�6�B*CJOJQJ\�^JaJmH	@phsH	@4h�Bh�Z�B*CJOJQJ\�^JaJmH	@phsH	@4h�Bh];�B*CJOJQJ\�^JaJmH	@phsH	@4h��h��B*CJOJQJ\�^JaJmH	@phsH	@4h�Bh�ScB*CJOJQJ\�^JaJmH	@phsH	@
�����4h�Bh�2�B*CJOJQJ\�^JaJmH	@phsH	@.h��B*CJOJQJ\�^JaJmH	@phsH	@21�h:p�2���. ��A!��"��#��$��%�������b&���������666666666vvvvvvvvv66>6666666>6666666666666666666666�666666666�666666666686hH66666<6666666666>>6666666666666666666666666666666666666666666666>�666���� 0@P`p������6(66 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p������ 0@P`p��8X�V~PJ_HmH	@nH	@sH	@tH	@b`�b�2�Normal�9�9d]�9^�9$CJOJPJQJ_HaJmH	sH	tH	l@l�2��	Heading 1$$��@&/5�B*CJOJPJQJ\�^JaJmH	ph6_�sH	d@d�2��	Heading 2$$��@&'5�B*CJOJPJQJ\�^JaJphO��Z@Z%Y'��	Heading 3$���<@&5�CJOJPJQJ\�^JaJDA �D
Default Paragraph FontRi�R
0Table Normal�4�
l4�a�(k �(
0No ListR�@�R�2�0Balloon Textd�CJOJPJQJaJtH6B@6�2�	Body TextCJaJh"@h�2�Captiond�]�^�a$,B*CJOJPJQJ\�^JaJmH	phsH	R@"R�2�0Comment Textd�CJOJPJQJaJtH@j@!"@ �2�0Comment Subject5�\�d^@Bd�2�0Normal (Web)d��d�d[$\$CJOJPJQJ^JaJtHAB'`�QB�2�0Comment ReferenceCJaJ.X`�a.�2�@Emphasis6�]�6U`�q6�2�0	Hyperlink>*B*ph�*W`�*�2�`Strong5�\�J�o�J�2�0Comment Text CharCJaJmH	sH	V�o�V�2�0Balloon Text CharCJOJQJ^JaJmH	sH	`�@�`�2� List Paragraph��]�^��m$CJPJaJmH	sH	tHR�o�R�2� List Paragraph CharOJQJ^JmH	sH	z�O�z�2�0sample-citationd��d�d[$\$]�^�$CJOJPJQJ^JaJmH	@sH	@tH	@|�o��|�2�
MDPI_3.1_text$��dG$H$`��a$,B*OJ	PJQJ	_H	aJhmH	phsH	tH��O���2�MDPI_2.1_heading1!d���x@&G$H$]�^�35�B*CJOJ	PJQJ	^J_H	h�mH	phsH	tHV�o�V�2�0Comment Subject Char5�CJ\�aJmH	sH	f�o�f�2�Default!7$8$H$1B*CJOJPJQJ^J_HaJmH	@phsH	@tH	2�1"2�2�	lofigures"a$p�O2p�2�loftable#$$dh���a$,B*CJOJPJQJ\�^JaJmH	phsH	,��A,�2�
aut_con_in^�o�Q^Y'��Heading 3 Char*5�CJOJPJQJ\�^JaJmH	sH	tH	PK!����[Content_Types].xml���N�0E�H���-J��@%�ǎǢ|�ș$�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"/>#f�����^~	�.]��O",�1rK�O�P�QwR.STU�V9W�X�Y[l\b^�_�a�cnf�h�j�lPn��A���8:;<=?@ABCEFHIJKLMNOPRSTUVWXY[\]^_abc�(,N�V!c�9>DGQZ�L�#����@�����������0�(	�
��B
�S����	?�>EFK������:AKT]e>FQT������x}g�������#t�������������U_������**:+E+�,�,-!-(-3-�-�-e.w.�.�.T/a/l/x/�/00#0'131�1�122\2a2p3v3{5�5�6�6�8�8�9�9==�@�@�C�C�E�E�EFFFFF(F.F�F�F�F�F�F�F�F�F�F�F~G�G�G�G�G�G�G�G�G�G�G�G�G�GHHHH.H3H5H<H=HBHMHSH�H�H�H�H�HI�I�I�I�I�I�I�I�I�I�I$J'JPJWJYJ_J`JhJjJlJ�J�J�J�JXK]KcKhKoKvK�K�KLLLL L'L@LGLHLKL�L�L�L�L�L�L	MM4M;MvMzM{MM�M�M�M�M�M�M�M�MhNqN�N�N�N�N�N�N�N�N*O.O/O3O4O=O�O�O�O�O�O�OPPAPQP*Q.Q/Q4Q5Q?Q\Q^QdQlQ�Q�Q�Q�Q�Q�QRRRR"R$R&R)R2R:R�R�R�R�R�R�R�R�R�RS$S0S~S�S�S�S�S�S�S�STTTTT T!T&T/T2T�T�T�T�T�T�T�T�T�T�T
UUqU{U|U�U�U�U�U�U�U�U�U�U�U�U�U�U�U�UV#V$V/VIVQVYV_VgVnVoVuVzV�V�V�V�V�V�V�VW
W+W0W3WAWCW\W]WfW�W�W�W�W�W�WX
X5X9XHXQX�X�X�X�X�X�XVYZY[YaYcYiY�Y�Y�Y�Y�YZ	ZZ�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z�Z[7[8[A[�[�[�[�[�[�[�[�[�[�[�[�[+\;\<\E\�\�\B]K]�]�]�]�]5^8^F^Q^k^o^{^�^�^�^___%_2_8_B_[_\_e_{_�_�_�_`````!`m`�`�`�`�`�`�`�`�`�`�`�`�`�`�`�`�`aaaaaa$alawa�a�a�a�a�a
bbbb%b&b-bFbQbRbVbeblbnbsbtbzb�b�b�b�bccDcJcQcYc^ccc�c�c)d-d.d1d2d9dZdadldud}d�d�d�d�d�d�de:e?eAeHeIeRe^eceheneoete�e�e�e�eff
ff%f,9GJ[�
��IL�&�&�'�'s)u)4+7+�-�-�/�/D0G0�9�9sG�G"HTHUH�H�HmI�K�KLLLML�L�LMMsM�M�M�MgNdO�O�O[PXQ�Q�TiUVVEV�V�V1W2W�W5X9X>Y�Y�Y�Z�\<]1^�^�_3`4`�`Bb
c'd(dNd�d%f33333333333333333333333333333333333333333333g��	�	�	�	�	�	�	�	�	�	�	�	Rdeee1e{e~e�effff f!f"f%f�Cp��Cp����������s���s������������Lm�2�������������W���^��`�W�o(.���\���^��`�\�OJ
QJ
o(l������^��`���.������^��`���.��p�L�^�p`�L�.��@���^�@`���.�����^�`���.����L�^��`�L�.������^��`���.������^��`���.��P�L�^�P`�L�.s����Cp��Lm����������������	@	@	@	@	@	@	@	@	@�'� hi?�9�?Zr�?Q?�D8��g$�T�rB�P[p(
�K5D��v.{B2	�

�
�R
�Z
8q
@@\�NJZ� 
F
�a-'FB�%�r�}H+WT
[�hCq�x~�=�S�$�l�b�|-"gl�)�h,�fUD /F �M A#! 
#M#�e$�y$�&%@%DK%�w%�x%�V&O\&!n&�)bC)B
*�j+�6,�7-�s.u/ )/*/`w/�060nV0�n0�s0+2MS2023Cg3�k3�4s^405>C5{b5u86�=696�L7
r8C 9#?:M:Ve:�M;�8<G<�I<�w<�=,'=R=�R=�?j+?&#@t+A�Bz
B�|BjKC�vC�2D�
E8EzGReG9|I3fJ�lK�zKA=L�tL
+M&LM.dMw1N*;N�=N�_N�]O�P\<Q4R�|S�EUzrW�VX�cX�YY�Y�1Yt])~^6`�H`�p`�eb,xb�
c@6c�6c�Sc�"d4e|e[f�gc-g�1gXKg�Xg�yjkDKk�\k�-luql�mNmL/nob!o�p%qMPq�pqbrpUrtt�1t"6t0:u>u�Ku:Tu�Lv�dv�w&x&7y�=y1z�1z�Az\z�pz�F{|�}�K~9�5�wt���e9�<��_��!��S��_�p��c��g��-�HE�>T�����e����<��4���;�^b�U8��k��n�2r��E�2#�#2��%����1��`��t��"�VZ����Q��2��f��y��%������b�^����3�4H�l��r~��V�y�7�;�tA���r%��Z�];��T�BW�Qz��f��
��:��Q�ph��r����!�,(�zo��v�ic�2q��s�2�y�V>��>�/R�5S�sj�p}�b�g(�W�.�::�iO��
���W+�B5�(7�y�7�aV�y� ��G��}L��V�t6��H�>d��A�����+7��w�����l	�ZW�� ��9��V���Y��Z�3�"8��}����R=��`��6���\Y�.��_��#��v����V�3���G�P��q��8�,B��D��2��W��<�:s��|��;��0��_�bg�z�Q.�nS�}z��|�a��t�}X�WG�p�bs��%�SM���1��W��[�c]����z��}�N�_��Y�a�&P��D�Ii�P��4�WO�3T��\��a�Yv��<�M����Y���KU�&h�#�T&�Y'��i�n��s�O!��V�n/�s]�>-�����'P��v�_��=�[��#��9�,��R�%u����Z�Z��W� Q��Y�>d��K��k��s�m����k�,2��C�[X��G�4t��8��{��K��r�����I/��A�>U���:#�/w�(P��j��n;QF�S��n�Li�l�V(2u�|4Sv�p��;�a2�&pS�,]�8�8�.(��l/�.f_��q��F_	�=�	�Y�	�h
�Q�
�K�/^�'}�~,�`d��;/�HB
>�
�4�
8�
1%/�HV�
[���9&
:B�5%� rpP�k��TI�$f�*�;R��Xa�g�
o0��{�jo4�A+�r=1nC�d��'��'!�Y��\�pv��V��a�\8i �!#�VT�{���)&j�;���Bs>T��B5o3�]z�ff��-f�&||s�O� j@�!�M�!�"Y,"�J�"3i#&9?#U>R#��#k�#�
1$�
9$�G$G|~$g"�$�Z'%ClL%�Tt%�+�%�8�%�&<y'U`$'�0'�aw'�'�'�*�'�(e#)0t,)��)`*`y�*P)�*I(�*�E+e-?z	-��-��-�f.X,�.�E�.�:�.X/]
/M�/��/W0y0])�0YL�0�$�0LB1��1�2't2�3�b4_G4j�4A
50'S5W�5�&C6�_�6Vi@7�o�8�l9�R�9�(:PR�:=�:T~1<gH<��<��<`(�=;�=�0>�e�>�I�>h<�>�?t�?�Q�?�l�@y0�A#+B~D
Cx6VC3yC�uD�D��D�JE�$qE�=�E�_�F�_�F�K�G�b�GO4�GW;H<
�HY~I�}IhK�IUf�I!J"iJ�QK*ggKv�K"J2L��L��M�B�MyKN�VN�.|N�DOB�Oi�O�T#P�U�P�j�P�	Qgx�R��R�3SdS�NT�\]T:w�T�4V�'W�o?W�}eWEDiW�arWQ=�W��WlX�{X6?MXtJ�X�1�X��Y�w�Y�J�Y�qZ�>�ZuX�Z��Z0R[7g[�Ph[aV�[�[z\�|<\�oE\�3�\�I_]�_�]	vA^�7�^�u�_�{o`�Q�`gkbah�a3@b(I{b�6�bXM�b^l�b�cN;-c�%�dR9�d�+�e�T�el�e0[>f�:�f�R�f�Cg3Dg�_.gl6dg"&�g�bh8Z"hW�h�Bim;Li�$�i�q�i:Obj�@�j�N�j��j	k�%k|�k�o�kc9�m�)in�Z�n�	o�11oT?�p%_q�P|qiw�q�ir�y6suos>�s� �s�Sktwt�l�t�0Nu,ivur�udC�u]v	vF3)v�dUw
}w�q�w�p�w�]x�cgx�|�x�['y�"�y�h�yA�y~Azl@�ze{�w�{)t�{�m|�)/|d{�|�+8}�Hc},<�}�g~yr�~6A'�eF!��
�#f%f�@�����dF#F$FVFWF[F\;d#f�@�,�\@�`��@�f��@��@��Unknown������������G��.�[x�	�Times New Roman5��Symbol3.��.�[x�	�ArialA.���Arial NarrowA���$B�Cambria Math;���(SimSun�[SO7.��.�{$�	�Calibri7���$B�Cambria5.��.�[`�)�TahomaK���@�Palatino Linotype;��Wingdings"q���hz2��ۑg��>�V4��>�V4�1�������20�e�eO�Q����HP	�$P�����������������������V�2!xx����Shrishti PrakashSHALINI����Oh��+'��0`�������	��
(
4@HPX�Shrishti PrakashNormalSHALINI172Microsoft Office Word@�}�>@Mܺ;�@�Qz��>�V����՜.��+,��D��՜.��+,��4�hp��������
���Microsoft�4�eTitled ?GKSOProductBuildVer�1033-11.2.0.9255	

 !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcd����fghijklmnopqrstuvwxyz{|}~���������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������Root Entry��������	�F ��)z����1Table������������e�EWordDocument��������4�SummaryInformation(�����DocumentSummaryInformation8�������������MsoDataStore��������P�)z��p��)z��5X�X�V���UCRPD�UH�V5��==2����	P�)z���ӹ)z��Item
��������Properties������������F�A��0��0�EO�W��I0O��5Q==2��������
P�)z��p��)z��Item
��������
�Properties������������U����	����
����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������<?xml version="1.0" encoding="UTF-8" standalone="yes"?><s:customData xmlns="http://www.wps.cn/officeDocument/2013/wpsCustomData" xmlns:s="http://www.wps.cn/officeDocument/2013/wpsCustomData"><customSectProps><customSectPr/></customSectProps></s:customData><?xml version="1.0" encoding="UTF-8" standalone="no"?>
<ds:datastoreItem ds:itemID="{B1977F7D-205B-4081-913C-38D41E755F92}" xmlns:ds="http://schemas.openxmlformats.org/officeDocument/2006/customXml"><ds:schemaRefs><ds:schemaRef ds:uri="http://www.wps.cn/officeDocument/2013/wpsCustomData"/></ds:schemaRefs></ds:datastoreItem><b:Sources SelectedStyle="\APA.XSL" StyleName="APA" 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="{6B7F0BC4-1A1C-4394-A55B-D84868ED637D}" 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�qCompObj����r������������������������������������

Youez - 2016 - github.com/yon3zu
LinuXploit