O O Aline Witaicenis HO HO O HO O HO Estudo comparativo dos efeitos de esculetina, 4-metilesculetina, prednisolona e O CH3 NH N sulfassalazina no modelo de doença inflamatória Sintestinal induzida por TNBS em O ratos O N N OH O CH3 HO CH3 Botucatu 2010 O OH OH OH Aline Witaicenis Estudo comparativo dos efeitos de esculetina, 4-metilesculetina, prednisolona e sulfassalazina no modelo de doença inflamatória intestinal induzida por TNBS em ratos Tese apresentada ao Instituto de Biociências da Universidade Estadual Paulista, como parte dos requisitos para obtenção do título de Doutora em Ciências Biológicas, Área de Concentração: Farmacologia. Orientador: Prof. Dr. Luiz Claudio Di Stasi Botucatu 2010 FICHA CATALOGRÁFICA ELABORADA PELA SEÇÃO TÉC. AQUIS. E TRAT. DA INFORMAÇÃO DIVISÃO TÉCNICA DE BIBLIOTECA E DOCUMENTAÇÃO - CAMPUS DE BOTUCATU - UNESP BIBLIOTECÁRIA RESPONSÁVEL: ROSEMEIRE APARECIDA VICENTE Witaicenis, Aline. 1 Estudo comparativo dos efeitos de esculetina, 4-metilesculetina, prednisolona e sulfassalazina no modelo de doença inflamatória intestinal induzida por TNBS em ratos / Aline Witaicenis – Botucatu, 2010 Tese (doutorado) - Instituto de Biociências, Universidade Estadual Paulista, 2010. Orientador: Luiz Claudio Di Stasi Capes: 21006008 1. Intestino – Doenças inflamatórias. 2. Produtos naturais. 3. Colite. Palavras-chave: Esculetina, 4-metilesculetina; Inflamação intestinal; Metaloproteinases; Prednisolona; Sulfassalazina. 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A 3 )99Y8 N B - * + 7A " " !" ? ! - 5- ( ) *)C 8 1*+ ( - 5 3 4 34? - 5- - - - ( - ( - ( ++-( -*+ 8 &' $ D D 3 4 34? 3!-; D ??!" " 3 - D <= !6? ! " , 4 ), *+ & - " 3 4 3 A " 5 - ? " 4 [ - 4? ? !)99Y8N B -*+ > 3 3 4 34? 4 " 9 3 3!-3! 3! = = ? ! )' -*+ . M1.&&&- > 4 3 " 35+ ?44? " 3 ? D 5 - <"3 4 -3 4 = " - ;=A= - ! A" )9YD N B" - *+ ? 3 = 4 ? 5 ; " 4 =4 - ]^ ,+ " 4 4 ? ? " )99Y8 N B - *+ ^ !" 3 5- , " " <" )'8 M*+ U ; G22 3 -;4;k - ; ? 3 4 )&3 N 9 &' H- *+ ? 3 ? ? ; 3 " ? ! - 5 <" ;k = )BF N , F- 1* !6? ! -; =D-9 D ? 3 - " ,-4 ? )H-1*+& 3 4 ? !" ==-"= )'? *+ ) :-: . > 4 5" - 5 Z <" D " " 6= =+ " " " "- ?" =?^+( -; " 6 "- <" 3 4 6 " - Z3 ? ! == ? ! ),Y -*+ G= 5 ; 4 =- ^ ? D - ; 4 =)(=F-*+ % ? 6- D ! 4 ? 3 ? - ; - ] )= * )= *- 4 5 ; " 4 - ? ? - 3 5 - <" 3 4 + > 34 5 " 3 - "A5 ? + > "A5 3 ? A <"< 10 &' ;3 ?< +RA ? 4 ? -D 4 ( 9-;" ? " )( -1*+ > 4 ? !"< 4 4 -] ?4= " 9-; ; )(=F-*+ > 4 ? "< - !?- !? " 4 8+ RA ; <? ?! H- ; 5 <" <? )( - 1*+ D ?! H- ?- " D - ; 4 " ?- 4 ! = 65 " ? ), F-*+ G?^ == ? + G ? " - 4 3= ? 4 ? ! !- ?!- !? " !?+ 4 - ^ G0m Gm !5 4 H )% -*+ ( ; G22+ (4- ;- ?! H- ? g " ), F-*+ ' 36- ; == L$ G + % G <= ? )H%/6d*- 4?)2%/6f*- )2C*2C62C6 -; L$4 3= 2C6M- 2C60- 2C6 2C6- 11 &' ;<3 9 G ; L$ )n= Fo *+ '3 )* =4 ? 5 9 - ; 9 A ? ?! H9 = H9- = ? ; + > == " ? ! 4 = -; = !6? ! - ; < ; " =A ? ! )( 8 0*+ 9 ; < ? ! - = ; ? ? " 4 ? ! - - " 5 5 ), N L 8-1*+ > 43 = !" "= " ?g3 4 <" = -?[ I ),Y -*+' 36 ; I == 3 4 " 9 = == ? ! - 4 = ; 9+ 5L &5 = ; ; ? "4 A == ? ! - G+G ""4 " ) = "9N( =-*+& G- ? 3= ; " - Ml - 3 12 &' == -; = A "16l) N'3-*+ - " %>G )< "D <* 34 LGM )< M = * 4 " == G22- G)Bp *+ &5 1= ^"%>GLGM= L-L?+?5 " 4 9 - 4 36 ; A 9 < )C('* 3 3 4 " = 3;k = %/6q )>" *+ Bp )* = ; = ? 4 3= G A ? D = %/6q C('- ; G " <+ &4+=D ; ? ; %>G- J68K )HCL* A= 9 !"- ;k = -D 5 =A" = ? ! )29 *+ U <= ; " %>G HCL " 9 3 4 = + - = %/6q - = %>G 3 9 - 3 4 " - A = = - !6? ! -; == G)29 *+ 4 - ? "- >H% ) A "I* 34 9 'C0M- D 2 GM- 34 G)(8= 0O 1O7 O 299 *+ H " ; ? 13 &' 53! A =4 3 )(8= 0*+ >" 34 G4%CL( ? < % )299 *- = ; 5 A "? 3 D H% '- " [- 34 3 G )7 *+ ' ? 34 9 " " )299 *+ > ? "4 G22 4 5 ^ < ?" - 3 4" == = + @&E >? !"; = 3 = ? ! =+ > 5 = 4 ? !" 3 - ? = 4 = 5" )&L>'* " )&L%* 3= ? !+ &4 = 5"- ? 3 5"- 4 = - = g 4 9 - 4 4 ? 5 + > 3 = " 5 4 5 =)LD *+ > =3= ? ! . !5 < )%>*- !5 )>6*- !5 )>%>>*- !5 14 &' 9")B>*9)>*),TD 1*-!? L$! G- ? =)T N T9 1*- ; ]A A + & ; = = - 5 >6 ? Z !? ? - 4 == 3D A ;[+> B> ; !?- !- = ?! H- "" 3D A ;[)TN7 "-*+ > ; = 3 < 3 " 5 < - " ; ? " "- ; " 3 ;k +H 34 = " < - " ^ ? 4 +/ -; A4 ? =-6 " < < ? ^ "4 - ;k " == )L *+ & Z ]? I6 = )81*+ ? ! D !? !? "- ; ; = 3 =- ; 3 4 ! + & ? = " 4 ? "< ; 3 4 = 5"- 4 3 5 - ; ] " " A9 [+" D 5 < - =- A=== )G " *+ 15 &' G ? - 4 A= ? 5 <= = G22- ] 5 9 )T N 7 "- *+ & - " ; A = ? 5 !" )T3 8 0*+ )* 3= = ? ! 5 =- ; C96 F )1* = 5 ^ <= 5 = 3 ! ? + N& 3 5 - ? ?A 3= ; 5= " =A ? ! + ( - 4 ; 4 ? <= == ? !+( 4 ^ ? 5 ; ? DA6DA)TN7 "-*+ & 5 6DA< ; ? -=" 5 - " D- = &- ? =!+ - " 9 - D ]A 4 = 5 6DA ; " - < -AZ " < d6?- 33 3;)TN7 "-*+ > ? DAA 4 <? ? =+ & D !5 )'>G*- )H* " 5 )(>*)TN7 "-*+ 16 &' &^?!" = D 5 4 3 3 5 <=4 = 5" "+c ;3 ? 5 !" G22- 3 " ? ! )T *+ G ? - ;; ? ^ GL$ = H(> < + ?? N G )M* 34 <= - " D 3;6 G22+ 3 5- 3 D =- ] = 5 !"- DA DA- 34? ? ! )%NL 86, -1*- 3 " ; =?A + 7.K&= D ? ! - " Z ?A - ; - "!- - )i 6/9-* 3!" ),+-*+2?D- <= G22-; ?A <= 4 ? - !- - 5-?5 3- ; D - 4 5 ; 9?A 5+ % - D "!-?;- 3!" )GY?MO 6'^ O'D *+ 17 &' > = A M6 < )M6'*- ; ? D - 3 D - D D + & ?A ? AM6 < " D+ ? D 4 ?A 9 = = - = = ),+-* = G )% = N B - *+ > A g = ? ! - = 3 < " -3g 5 )(-0*+ ? D D = - 4 = " Z ? ; + & ? 3 - A 5 - ; <= 4 ? - 4 - ^ 4" - ?3- 9!- )L ? N C " - *- ; " ? = ? D - ; 34 ?A + &5 34 = ^93 -;9 - - - ?4 ; ?A )(-0*+& -?9 6?!5)C * ? ) * ?A + > "! ! ?A ? ? ! D = = = 9 )% = N B - *- ?A D +> " ?A " 4 ! ; " + > 5 6 != ? <;" Z 4 " 6 G%-? " -D < " < - 18 &' 5- 6- 3 < - (6 %/q ), 5- M*+ G= - "! ? ? =A 4 == ? !- 5=A - ; - =- 4 - !5 < D<= )%>'* 5" )>E6* )L"- *+ ' = ? ! D 3 = ? - " ? !- = - 3 = ? ! ) N H " - 0*+ & ?A " !? " A ? - 3 2C6 !- 2C6 H%/6d ?!- ?? " )'9N( 8-1*+ G= ? "! - " - " A G22- == " = ? -; 5B()L"-*+ G ? 3= 3 < ? !- Z3 A63 - 3! - ^ 9A- = - Z6;4- 9" - 3- == 9 - ; ;k ! = ?A + / 34 " H2 == Z 4 - 4 ^ 3 " ! - 3 ?^ 9A )% = N B - *+ 4 ? 3= - ? " Z -;? 3 = <? ? D)'9 9 -*+ 3 "! = G22- ? - 4 3 ? - 3 ) 6'^ *+ 19 &' > D 16 34 D G22- ? = - 3 G L$ )L"- *+ - ; 4 3! =- !5 - A" =3 <G%+( - ^ 4 ?A )L " *+ ? - ? 5 ! - == 3 - 4 == ? )% = NB -*+ > 5 - !- 34 D G22+ > 5 " 3 ? - ? - ; 4 A <G%-= ? G%?- ; - 4 H+ G ? - 9 ?5 ?3 )L"-*+ > " 6H%/- 34 3!" ?A - D G+G D ?5 3- 3D 3)iNB -*+& ?A ;4- 6H%/; ?A G- 3 ?< )% = NB -*+> D H%/- 4 = 4 H !? " = )(3 *+> ? == - ?^- 3 ^ ? ; - ? - 4 - 3 ?3- 4 ^ ?A )% = N B - *+ 4 ? - 5 ; - == 20 &' I 3!" )i N B - *- - ; = 3D 3 + = M6'- !- 3!" 3?< ? ! - ?A )% = N B - *- ?= A =- D ? ! [ " < )i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l)2M* 5 < -= 1-M 1-μ,= ) +-*+ G ? - 06 = < 9 = 5 )( FA+--'9 M*- 4 < = ? ! 3 = 5" 5" 6=)'8= *+ & 3I - - =A ? !" - = 5 ? ===A =-? =+ & ? ,G) <* D 6369!5)6 B(*- =G((B)-69F66 9 D* )C *- " G% 5 = )T 8 *- 3 95 = = G% B>)T *-3 5 5 =)C *+4 = - " 9 5 6 B(- ? !? <= " )C *O 3 < 35 - I !5 !? )&" *- "" ;A 23 &' )>8 M*- = ) 3 *+ ( ? . !? " ?! )C" M*- 3 ) " +- * )( 8 *4 9 4 )i " +-1*-3 [) 3 * 4 '' I )T8 *- ?3 3 <= H/6e ), 3 ] * 3 5%/6q = < 6)(6*)( *+ 06 = 3 ? 3I < A 9 [ " I A )B ] *- = 5 Z - ? ) M* " ) *+ 3 = 5 - 06 ? = = ? ! 5 + % = = = < ? 5 ? ! D A 3D?[ )H% '* - ? " [ +&; 3I - M"T"- = ? ! 5 = A 5 ? ! 3I ) +- 5*+ & - = = ? ! - ; "- 4 ?A = <- ?A ? D G22 9 - ? D - ? ? ? !" ?A ? ! D H% ' + 24 &' <&.N .&&7. K .&-O&.%& 1O-.7PQ0#) & 5 ? ;<+ 4 3 6 9! ; G22 3 -;? <" I ! - ; 4 ; !"+ > 4 3 H% ' Ml- ; " J3 K-; ;AH% '- 9 - ; 6 3I - < - D !" ) = *+>H% ' === ? = - " ! -Z " ? - = " + &5 4 ; = = ? ! - 4 ; ? ; G22 9 )R] 0*+ B" - ? D H% ' 4 D Z ? - - 4 ?- " )/"4 1*- - -? 4 ? ! + ; -43= = D 5 )'A96B " * ?? )'A9D, -0*- 4 5 !6? ! H%/6d )'A96B " * -3 ^ 5 + 25 &' '"'3 -)*- ! - H% ' 4 4 H 4 <" I ! + 9H% '= 2C6 4 H9-;D 2%/6f- =D " !? "D !6? ! -H%/6d-2C6e2C6 1- ; ? ! )/" *+ 4 - =A ? ! == " &-35 - 00 )V9" *+ D H% '4 5 ? - ; = ? A <"<?)'3 *- 3 = = - Z G = - = = == ? ! + # $ !" !" % ȕ&' Į Ȗ ȕ -/&&-&&7. K ..0#) (r4 <"O((r( (FOHr4 HO,r !? "+ ) '3+-* 26 ,*7 ,*7 -, 3 53]= 3 9? . + = ? ? ! = < ) 06 *- = = ? ! O + = < )?A *??A ? D G22 9 - ? D - ? ? ? !" ? " - [ = D H% '-=; "?A ? D O + = = ? 0 3 I <- !- ! 3;< == ? ! [- ? ? O 0+ = ? ? 3 - ? !- 5 + 27 % %< % %< . L 9 3 "- 4 $- - ' ( ? D = ? ! + > ? 34 G / " - 2 - $- M < 5+ & 34 3 ±@ 69 +> ? ] 5 - "- A5 1 5 ? ( C 3'+2+A" +> ? D 5 = U &5 2)(+00#&&*+ )-1 R &2N . & )1-6956 *- 06 )1-6956066 *- ? D - /" -? 3 '" - 3D l- ?5 3 5+ 28 . -$ - -?-=&-1 R O HO O HO O O HO HO CH3 & 06, O CH3 O NH N S O O HO OH OH CH3 N OH N OH '? D O ( . & && & -. 4 9 .-. 4 &. -.7.O7-&&7. K . % ? " ? D " " 5 . A. 3 . B. . C. 6. + M"T" + 06 M"T" D. ?A . G+ "T" G+ ? D M"T" 29 . ? ! ? D 4 , )*-; ? ^+ > ? 3 < ]] 0 9 I "A > ?<+ &" -? D ) [ *-M "A-0-163D?[)H% '* Ml==+ ? D ] 4 )I *- ; ? D I 4 I + > ? 3 3 5 9 4 +> "3 ? 3 - 3 H% '+ > ? = D 6 ?A" -? D g1--0-09 +> "3 3 l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s ? "? s ? < 0 G < ? M G < ? < ? ; " 5! 16 ' ]<D 3 ; " 5 ! ) 4 < * ! A ! - ! ? = ? " " - ? " #@ < = 32 . ?? - - 5 - H%/6d- 2C6e Z <[-; ? "? <=" + .K& &K. 2 ! = ! ? ! [- )-M* ] g A ? 9!"+& ? ?5 ? 0l09 - = A" " <- 4 ! < - ? D 5- < ? B6 ( 9 ),861* +>-1[ - ? ?D D 4 ! < + "- ? 3 g 69 5 A ?!" ^ < ! 4 '9 )*+ I 9!" ? 3= !!?" ? !!C cY (=++0- E+ 33 . 01.+4 = ! [ + E.& /- , , L. +$ .)*%9O' =)*O, )*O'=)* += ,! .)*%9O' =)*O, )*O'=)* +G,.)*%9O' =)*O, )*O'=)* 0+2? , .)*%9O' =)*O, )*O'=)* ERK M+2? <.)*%9O' =)*O, )*O'=)* 1+7 .)*%9O' =)*O, )*O'=)* +2? , .)*%9O' =)*O, )*O'=)* )-1- +2? <.)*%9O' =)*O, )*O'=)* +& .)*%9O' =)*O, )*O'=)* &,A5.-? '9 + &S&L.-. K & > Z 4 ? 4/")/"NL38-0*+ 9!"- ? - ? 1 [ - ?D D 4 ! < + "- ? = A" ? g 1@ B % 34 g 1@- M + ! ? = = 5 A" + ! ? 3 = '9?- ? " 0M + G <- ? = A" + ( 5 A- ? = = D l- M + > 9!"?= = D 4 ! < + A Z 4 ? D ! ! 0E-? 9!" 34 . 5 - 5<3]= " < +/ Z Z4 + / 4 ! ; ; = -] -Z! D = 6!5 3 - ? ?" M+> ? 54 " Z 4 ! =Z + -./" ? ! "5 ? " + 4 /" + 4 ! ;+ ?" ? !!C cY(=+0- 0E+ 35 . M1?-= H ^ 3;< ? D 9"D [ - D ? 5 0M "- ] 9"D A-=?! = + & &&&.N&Q/< = 5 ? "! ? D 4 T YD )0* 5 5 " - = ,(>4 ? ; ;" t!59" M+ = 5 D ? !?- ; D ] <? + # & S&&.- . Z " ? D 4)M*-;A3 5 " D )'B* g ? 5 )''*- 3 A 33D! )GH% *+ > GH% D ; -; ? + > '' " 4 D D " %G(B+ > 'B ? 5 = - " <- ; = GH% ) ;k 33I 0* 4 g ; " )'Bm''*+ > ? 5 " + 36 . , & = & &&&77 .. Z < = ?? ? D 4A'9 )M* F )01*-= + & S&&..&.&=&Q/.P Z < [ ? D 4V" )*-" " ? ^+ ? 9"D T +Ml .M+>9" ??" 0@+ / D 0t3 -;? 3= - 34? t ? !+l-Mt A 4 l- B +M- M t A 3 3Z +l < A 4 0 t A" + ( = - ? D t ? ^ <- t A" "+ > ? ? 3 96 M@ 9 + ! ? ? ? ?" 0 +t3 ? 1 ? D ?[ M+>= ,G ? M ? 5 " + 37 . $ & . = " < ),,(* # 6 ! ?"5 ? D" ? " " +( 5 D - " - H6BM,-B+M- -Ml H E6 , ? 9"D ( M " + > 9"D ? 3 " 9 0 ? 5 +!<- 9"D ??" +L(,M 0+>3 ? = Z < ? ; ? 4 ? )1*+ 5 )u"< *? 3 g?-3 ^ 6 - " l D +l " + G ?- "4 ? = =D M +Ml H E6 = ? ! )'G'*- " = " M 6B M ,- B +- M, ,V+(-"4? 3 60 9 - 3 " + ? - "4 ? L6M+> = 3 ? D D ?+ A ; = ) ! " # 2>G* 3 3 D" ? ? D D 62 ", 7G' =+ 9 2 ", 7G')(9 9*+> ? 52>G+ &=&09T:E9U > <= H%/6d 2C6e ? ! - 9"D ( ' ) ?? !*- B 38 . +- ).M*= 0@+!9"D ? " 3 96 g@ !? ?" +M 0@+>3 ?9 D ?D 6@ 4 D "+><=H%/6d2C6e? 8 )&C2'*-= 3? 5""< )L"D6 3D *+ .& &&&$-. 9 .-. 1& K97. K ( = ? 06 - 3 !6? ! ? D 9 " . 4 9 ) 6*- !? " ")L10+* 4 =A-3 ?!3 " 3v+ 4 ) 6*- ; 4 9 " 4 9 - 9 " L10+? 3 '== $= 6& 9 +& 4 ? @-Ml > ?4 = G,&, )G3v ? & "v * -C6" ),*- )M$C*- ? )-M"C*l? 3= = )0-M1*- ? G,&%+ 4 =A? 3 ?! " 3v " "+ ! - 3 ? = = 3 5 + & ^ 4- !" ? = M G,&, l 3!) *+ ] - 3 ? 4 ? 4 = + & " - )m4 * ? 9"D ] " "9 3M 39 . - ; ? ?" M M + > ? M )%B0-C-TB>-C- 6 4C*g0@-3]= !+! - -;4 ?! !? ")!*-? ?" MM" ? M G,&,+ &)&, K9:7. K ? 2C6- 2C6e- 2/%6f 2C6- - 06 ? ^u,-u,-M>u, u,+ ( 2C6? D 4 6+ & 4 ? 3 - < 0 9 - 06 ^ + ! < 4 ? 2C6e ) "* < 9 + G - 3 ? ?" g + & " - ? ?D6@ <=2C6 & ) 2 -%=- "*+> ? 5 2C6)"*+ ( 2C6e? D 4 L)5M 4 *+& 4 ? = 0 ? ^ = <- C(')M"*+!19 -3 ? 6@ 4 D +( <= 2C6e ? D T & ) *+ > ? 5 2C6e)"*+ ( 2/%6f2C6? D !)-M 9^4 *= 0+$ 9 40 . = )Mu"*- 4 ? ? ^ 3I + ! 0 9 - 3 ? 6@ 4 <= 2/%6f 2C6 T & ) *+ > ? 5 2/%6f2C6)"*+ #D1.&&,.-. ( = !5 3I - ? D = 3 3?4 D + = 3 4 6L10+? 4 = -"" E )*- " ? ^+ 4 ? ?5 = )+l* )l* g 3+!0 = "( '- 4 ? ? ! )'G' l* + (- 4 ? ?" M + & " - ? ; ? &C2' M0 + 4 =A= D 3 )29F 1*+> ? 5l= 3 + = 3 ! ? D L " 'H6 )L9 G "*+ & 4 4 = 3! ? +> Z=)'H6* 4 - ? " =A=- + c ? - = - ; 9! = 'H6- - ; 4 0M+ 4 = 3 )!* ? = 0 )-M 5 1 4 * -M 4 - ? = ) * )Mu"* 0 9 + H ? 41 . Mu = 'H6 )L9* 9 @ + & " ? " ? ; ? &C2' M0 +> ? 5l= 3 !+ %. = H ? 5 4 w 4 )&+(+,+*+ G? 4 ? A 7 I )%>7* " "?I + G 4 )* ? 5 ? T8 6 "G+ G < ? E+ "?I < ? = x-M+ 42 I I % @-. &&.N .&7-& ./K [ H% ' ? 4 [- ; = ! 0 9 - 6 + # M+ " !- = 9 + & I ? 5 ? - 3= 3 + > ! ; " )1 =+ = - x-M*+ > ? D - 06 34 ? " ) 3 *-49 ? < ?3= + 5 -" 5 4 0-1w-01- 3I 5 ?- 9 ? < ? 3= + = 6 [ )"*- " 00-1Mw0-0 " =+ -w- " 3 ) <*- ? < x+- 49 = I+ > " l 4 -; ; 4 -l+c g - ?3= -l " - -l - 06 ? D - 9 ) 3 *+ 43 $ K Q+9+ zzz -)6* -M)M6* -)6* 1-)6*z 1-M)6* $N @. L &' &. * QV, QV, Q1 Q*1 zz -w-zz z z 0-1w-01 00-1Mw0-0 - - 0-w-M -wM-M -z - -w-M -Mw- - - -Mw-M -w- -z z -Mw-M -Mw-M 11-11 - 44 y>= 5 )= *- 35 - 6[ 54 w &+(+,+- 4 ? E- z x-MOzzx -Ozzzx - " + H " ? ? "? = " 3 x - )"?I 3 *+ $ K 5- Q+9 # -M)6*zzz , . 1-M)6* $-. -)6* 9 .-. -)60*z &. -M)61*z )-.7.O -)60* 01. + = I ! ! ? )M"T"*- 06 )M"T"*- )"T"*? D )M"T"*5 " ? ! D H% ' + % % ! H% '- ? D- ; "3 )<* 3 ! ]] ? ; " ; "+> 06 3 ! ? ![)x+M-? < 3 *)/" 1*+ # Média de consumo de ração por animal (g) 25 , . $-. Q*I 20 9/ .-. Q*I 15 &.Q*I )-.7.OQ+*I 10 5 0 2 3 4 5 6 7 Dias - . = "- 3 5 " D H% '+ G 5 Z + ? !- " 3 3 " 9 ]]+ > 06 - ? D 3 " 9 ! ! H% ')/" *+ Delta Peso dos animais (%) 14 ** 12 10 8 6 * ** 4 2 0 -2 1 2 3 4 5 6 7 Dias -4 -6 -8 - .= = 3 5 " D H% '+ G 5 4 )( ? 6 * E *w&+(+,+zx-Mzzx- "H% '+ 45 % .K A9!" ; " = - = D - - )= * ? ? !3 I ! )=* 3 ) *- ? " <- ; < ? !+ > = D I ! - ; " + > 06 - ? D = 9 g =- = - ? " < 3 - ; 06 34= ? I ! )?" *+ & ? = " " '9 )* 5 ? !- ; 06 < "? = ! " 9 g? D ) 3 *+ 46 % ++W # ++W Q Q , . Q1 ++W ++W 9 .-. Q& $-. Q& Q1 )-.7.O ++W ++W &. Q& Q& -!./" ? ! ?"5 ! H% '+ 9 5 )B&*+ ,?" ? ! ! C cY ( = +0- ME+ = - =O - 06 - ? D - ? 3 + . Q = - Q1 ? 4 & ? ! 3 - Q " D ; - Q& ; + 47 % &L.-. K Z 4 Z ; " Z 4 ! " 3 + G ; = Z 4 ")/" *+ # 0,16 , . Células apoptóticas por cripta 0,14 $-. Q*I 0,12 9 .-. Q*I 0,1 * 0,08 ** &.Q*I )-.7.OQ+*I 0,06 0,04 0,02 0 -".= Z4 3 5 " D H% '+ G 5 4 w &+(+,+ zx+Mzzx+ "+ 48 % .M#?-= ; - ? ! = ! H% '- ;3= = ,(>)/" *- ? )/" * )/" *- 4 <= H%/6d )/" 0* 2C6e )/" M*- ; " < )3 *+ & 9 "? Z " [ )/" * Z < ),G* )/" *- ;k 5 = ; ! A3+ > 46 - 06 - ? D = <=" [ -; " )/" *+ = Z'B-9 ? < ?3= 3I ?A ? - Z,G )/" *+ > 46 06 - ? D = = ?? ; " )/" *- - 9 ? D = D 5 )/" *+ c <= H%/6d- D <= 0Ml )/" 0*- - 9 = "? = <=2C6e)/" M*+ = D ),,(*; = ,,(6 ? ? ! [ ? " = ,,(6 -; " 3 + > ? D 3 = ,,(6 34 = ,,(6 5 )/" *+ 49 % # 2500 , . GSH (nmol/g tecido) ** 2000 ** ** $-. Q*I ** ** 9/ .-. Q*I 1500 &.Q*I )-.7.OQ+*I 1000 500 0 - +. = <= " [ )'B* 3 5 " D H% '+ G 5 4 w &+(+,+ zz x+ "+ 350 250 200 150 100 50 * 0 - . = = D 5 ),(>* 3 5 " D H% '+G 54 w&+(+, zx+M "+ 20 18 FA (mU/mg proteína) MPO (U/g tecido) 300 16 14 * 12 ** * 10 8 6 ** 4 2 0 - = = ?? )/* 3 5 " D H% '+ G 5 4 w &+(+,+ z x+Mzzx+- "+ 50 MDA (nmol/g tecido) % 25 # 20 , .0#) $-. Q*I * 15 9 .9-. Q*I &.Q*I 10 )-.7.OQ+*I 5 0 - = <= < ),G* 3 5 " D H% '+ G 5 4 w &+(+,+ z x+M- "+ TNF-alfa (pg/mg proteína) 350 300 250 * * 200 * 150 100 50 0 - = <= H%/6d 3 5 " D H% '+G 54 w&+(+,+zx+Mzzx+- "+ IL-1 beta (pg/mg proteína) 6000 5000 4000 3000 2000 ** 1000 0 -= <=2C6e 3 5 " D H% '+ G 5 4 w &+(+,+ zx+M zzx+- "+ 51 % //9"K # , $ //9" //9K //9: & //9 -.= " < ,,(6 ,,(6 D" ? + ?" ? 2 " , 7G' )(9 9*+ r O rO r& OGr06 -&r( /r'? D + 300 MMP-9 MMP-2 250 IOD 200 150 100 ** 50 0 Branco Controle Esculetina 4-metilesculetina Prednisolona Sulfasalazina - . A 4 = " < ),,(* 6 ,,(6 D" ? - 3 5 " D H% '+G 54 w&+(+,+ ! )2>G*-zz x+ "+ 52 % @-. & & &. N . & & 7. K . & 7P& ./K 5 ? " - [ D ? 4 [ + ? ! D [ - ? ! ? - )3= 9" = 5 * ? " + & 4 A5 0 9 ! H% ' 3= "-D- 4 +! - ;3= 5? " - " " ! H% ' )H 3 0*+ %5 ? ! ? [ -; I !- ? <= 3= ; 06 !- - ! + > 9 - 4 "? = 5 4 )H 3 0*+% " ! H% '- ? <= 3= 5 06 = [; " + % ! = - - 06 - = 5 ; " - ? ?A ? ; = 9 9 "? = I ! = - ! = ? !)H 3 0*+ 53 $ K Q+9 0-11)6*zzz 0-)6* -1)6* -)61* -)06*z -M)6* -)16* $ $N K &. Q+9+ Q1 X) zzz zz M-M)M6* -w-M 0-)61* -w-M -M)6M*z -w- -)6M*zz -w-0z 0-)61* -w- X) z zz -)60* -Mw-M 0-)6M* -w- -)6* -w-1 -M)6* -1w-1z -)61* -w- X) zzz zz 0-)60* -w-M -)6* -w-z -)60* -1w-0z -M)60* -Mw-0z -M)60* -0Mw-0 -)6* -Mw-1 -w0-zz -w- 00-Mw- 0-MwM-0 M-w- -M0w- -w0- -w-zz 01-w-M 0-Mw-1 -1wM-M1z 0-w1-0 M-w- M- - - - - - 11-11 - M- M- - -w-0zz 1-11 0-Mw- - 0-00w-M - -w0-M - -0w- 1-1z -0w-M - - 1-1 - - - - - - - 1-1 - - 1-1 -z 11-11 - -z -z 1-11z @. L &' * QV, QV, Q*1 54 y 5 )= *- 3 5 - 6 [ 5 4 w &+(+,+ 4 ? E-zx-MOzzx-Ozzzx- "+H" ?? "? = "3 x-)"?I 3 *+ # , .0#) , .& $-. *I 9 .-. *I &.*I )-.7.O+*I # 0-0)06M*zzz , .0#) -)6* $-. *I -)M-* 9 .-. *I -)16* &.*I -)6* )-.7.O+*I -1)06*z # 0-)06M*zz , .0#) 0-M)6* $-. *I -1)6* 9 .-. *I -M)6M* &.*I -)60* )-.7.O+*I -)6* 5- )"T"*? D )M"T"*5 [= ? D H% ' + 01.+= I! !? )M"T"*-06 )M"T"*- % % % = -?3= " ; " 3 )6<*- ! H% '- ; ? " " )/" *+ H = " - ! ? !+ > = < ? D = " - ? 3-9 =? < " + > " = " 9 ; "3 )6<* -" + > 06 = " 9 ?A ? -; 3= ?" + > ? D - " 5 - ! = - " 9 ?)x-M* " + > " ? " M- - - - 0 + & ; 3 ? D ? " - 0 1 )? < ?" *+ 55 Média de consumo de ração por animal (g) % , . $-. Q*I 9/ .9-. Q*I 30 &.Q*I )-.7.OQ+*I , .& 25 20 1 Média consumo de ração por animal (g) # X) 35 3 4 5 6 7 X) 33 31 29 27 25 23 21 19 2 3 4 5 6 7 8 9 10 11 12 13 14 ! Média consumo ração por animal (g) X) + + + + ! " + " + - !. = 4 3 5 ? [ - - " ! H% '+ G 5 4 - " + G H% ' 0P = )]]*- + 56 % # . &&QV X) + ! + ! + ** , . $-. Q*I 9/ .-. Q*I ** &.Q*I )-.7.OQ+*I ** , .& 40 X) ** . &QV 35 ** 30 25 ** ** 20 ** 15 ** 10 5 0 -5 " . &QV + X) ** + ** ** + ** ** ** ** ** + ** + + " " 9+ - ". = = 3 5 '+G H% '0P ? [ = D H% 2. .K = - + G 5 4 )( ? 6 ( *E( *w&+(+,+zzx+ "H% '+ 57 % ./K % ! - " = ? <=3= " 4 ? ! - " < - ; - 4 = + % 3 34 ? <= 3= " ? 4 ? ! 34 )/" *+ > ? 4 ? ! I ! - " + % 06 - ? <= 3= 9 = I - - - ? ? !- 01-Ml ! ; "-49 ? < ?3= +> ? ? !- 3 +% 9!" ? D ? <= 3= ")/" H 3 0*+ % " ! H% '- " = ; " ! H% 'O4 ? ? !" < - = = = + > - 3 ; 58 % " - 3 ? + 06 = - ? ? ! + ( = - ? ? ! ; 3 - 4 + '? D ? ? ! -] ? "? = ! " )/" H 3 0*+ % - ! = - " = = - - - ? " < = I ! 3 + > " = - ] - ; 3 " H% '- ; = - ? ? ! I ! - = +> ;3 - - = - 3 ? " <- ; 3 + B" - ; 3 06 9 ; - ? D -? < "-9 I = + > ? D = - ? ? ! 3 - = ")/" H 3 0*+ 59 % X) # , . Q Q1 $-. 9/ .-. &. )-.7.O Q1 -+./" ? ! ?"5 ! H% '+ 9 5 )B&*+ ,?" ? ! ! C cY ( = +0- E+ = ? ? ! 3 + - ? D ? 3 + 06 < 9 " 3 + Q $ Q1? 4 ? ! + 60 % X) # , . Q $-. 9/ .-. Q1 Q1 Q &. )-.7.O Q1 Q Q1 -./" ? ! ?"5 ! H% '+ 9 5 )B&* ?" ? ! ! C cY ( = +0- E+ ? ? ! 3 Q ? 4 ? ! Q1 3 Q- [ -0 ! H% '+ 61 % X) # , . Q Q1 Q Q Q1 , .& $-. Q1 Q& - . /" ? ! ? " 5 ! = + 9 5 )B&*- ?" ? ! ! C cY ( = +0- E+ ? 3 + " Q = D - Q1 ? 4 ? ! - Q ; += ; Q&+ 62 % X) 9/ .-. Q &. Q )-.7.O Q1 Q1 - ./" ? ! ?"5 ! = + 9 5 )B&* ?" ? ! ! C cY ( = +0- E+ 06 9 " 3 + Q = D Q1 ? 4 ? ! + ? D ? 3 ; " + 63 % &L.-. K = 9!" ; " Z 4 ! - " ? !? [ -Z ; 3= 5? " +H = "? = Z 4 = )/" 0*+ # Células apoptóticas por cripta 0,25 X) , . 0,2 $-. Q*I 0,15 0,1 ** ** ** * ** 9 .-. Q*I &.Q*I )-.7.OQ+*I 0,05 Células apoptóticas por cripta Células apoptóticas por cripta 0 0,35 X) 0,3 0,25 0,2 ** 0,15 0,1 ** ** ** ** 0,05 0 0,3 # X) , . 0,25 0,2 0,15 0,1 , .& ** ** ** ** ** $-. Q*I ** 0,05 0 9 .-. Q*I &.Q*I )-.7.OQ+*I -.= Z4 - 3 5 [ = D H% ' +G 5 4 w&+(+,+z--Mzzx- "+ 64 % M#?-= % I 3;< = - ! H% '- 06 = 3 = D 5 ),(>*)/" 1* ?? )/* )/" * D <= < ),G* )/" *- ; 4 9 I- 34 = <= " )'B*)/" M*+> ? D = <= 'B )/" M* 3 = D ,(> / )?" 1 *- 4D<=,G)/" *+ c g = !6? ! [ - - D <=H%/6d2C6e )/" *- ; ; 06 <=2C6e+> ? D =9 "? I+ % = - 06 - ? D = ,,(6- 9 = ,,(6)/" *+ % " ! H% '- = <?A ? = 3 = D /)/" *+ ! = - = 'B 3 = D ,(> / )/" 1 *- ; ; 06 3 = / )/" *+ > = <= 'B )/" M*- ? D - ; 4 - 34 3 = /)/" *+ 65 % X) # 1600 GSH (nmol/g tecido) 1400 * 1200 , . ** * $-. Q*I 9/ .-. Q*I 1000 &.Q*I 800 )-.7.OQ+*I 600 400 200 0 X) 2500 GSH (nmol/g tecido) * 2000 1500 1000 500 0 X) 2000 GSH (nmol/g tecido) 1800 1600 1400 ** * * * # , . ,)@ $-. Q*I 9/ .-. Q*I &.Q*I )-.7.OQ+*I 1200 1000 800 600 400 200 0 - . = <= " [ )'B* 3 5 [ = D H% '- - " + G 5 4 w &+(+,+ z x-Mzzx- "+ 66 % 400 # X) , . 350 $-. Q*I MPO (U/g tecido) 300 9/ .-. Q*I &.Q*I 250 * ** 200 ** )-.7.OQ+*I ** 150 ** 100 50 0 200 X) 180 MPO (U/g tecido) 160 140 120 100 * 80 60 40 20 0 250 X) # , . MPO (U/g tecido) 200 ,)@ * 150 $-. Q*I 9/ .-. Q*I ** 100 &.Q*I )-.7.OQ+*I 50 0 - . = = D 5 ),(>* 3 5 [ D H% '- -" + G 5 4 w &+(+,+ z x-M zz x- " + 67 % 25 # X) , . FA (mU/mg proteína) 20 $-. Q*I 9/ .-. Q*I 15 * 10 * &.Q*I ** ** ** )-.7.OQ+*I 5 0 X) 20 FA (mU/mg proteína) 18 16 14 * 12 ** 10 8 ** ** ** 6 4 2 0 # 16 X) FA (mU/mg proteína) 14 , . ,)@ 12 $-. Q*I 10 * * 8 6 ** ** ** 9/ .-. Q*I &.Q*I )-.7.OQ+*I 4 2 0 - = = ?? )/* 3 5 [ = D H% '- -" +G 54 w&+(+,+zx-Mzz x-- "+ 68 % # X) 20 * MDA (nmol/g tecido) 18 16 ** 14 ** * 12 , . $-. Q*I 9/ .-. Q*I &.Q*I )-.7.OQ+*I 10 8 6 4 2 0 X) 18 MDA (nmol/g tecido) 16 14 12 10 * 8 6 4 2 0 # X) MDA (nmol/g tecido) 16 , . ,)@ 14 $-. Q*I 12 9/ .-. Q*I 10 * 8 &.Q*I )-.7.OQ+*I 6 4 2 0 - ! = <= < ),G* 3 5 [ = D H% '- -" +G 54 w&+(+,+zx+Mzz x+- "+ 69 % ) TNF-alfa (pg/mg proteína) 350 # , . 300 $-. Q*I 250 ** * ** 200 9/ .-. Q*I 150 &.Q*I 100 )-.7.OQ+*I 50 0 ) TNF-alfa (pg/mg proteína) 250 200 150 100 50 0 ) 160 , . 140 TNF-alfa (pg/mg proteína) # ,)@ 120 $-. Q*I 100 9 .-. Q*I &.Q*I 80 60 * )-.7.OQ+*I 40 20 0 - " = <= H%/6d 3 5 [ = D H% '- - " +G 54 w&+(+,+zx+Mzzx+- "+ 70 % # :E91 Q* = 6000 , . ) 5000 $-. Q*I 9 .-. Q*I 4000 &.Q*I 3000 * 2000 )-.7.OQ+*I * ** ** 1000 :E91 Q*& = 0 2000 ) 1500 1000 500 0 # :E91 Q* = 3000 ) 2500 , . ** ,)@ * $-. Q*I 9 .-. Q*I 2000 &.Q*I )-.7.OQ+*I 1500 1000 * * 500 0 -+= <=2C6e 3 5 [ D H% '- - " + G 5 4 w &+(+,+ z x+M zzx+- " + 71 % ) 200 MMP-9 MMP-2 180 160 140 IOD 120 100 * 80 ** 60 40 ** 20 0 Branco Controle Esculetina 4-metilesculetina Prednisolona Sulfasalazina ) 200 180 160 140 IOD 120 100 80 60 40 20 * 0 Branco Controle Esculetina 4-m etilesculetina Prednisolona Sulfasalazina ) 160 140 120 IOD 100 80 60 40 20 0 Branco Controle CSR Esculetina 4-metilesculetina Prednisolona Sulfasalazina - . A 4 = " < ),,(* 6 ,,(6 '+ D" ? - 3 5 [ = D H% G 5 4 w &+(+,+ ! )2>G* z x+M zz x+ "+ 72 % . & && & $-. 9 .-. 1 & K97. K % = 3 !6 ? ! -?<=3= ; t,3 2C62/%6f)/" 0*3 34 2C6e )/" *- 4 34 = M-0l 4 L )/" *+ 06 Mt, 3 2C6e- 2C6- 2/%6f 2C6 )/" - - 0 M*+ % = 3 = Ml 4 L )/" *+ % t, 06 3 2C6 e-2C6)/" *l 2/%6f)/" 0*- = 3 = Ml 4 L )/" *+ & 06 = = 3 ! 4 6)/" 1*+ + ,L.-. -.& E)Y/)< :E91 Q*. + $-. W/ $-. +W/ ++ $-. +W/ $-. ++W/ !+ 9 .-. W/ + 9 .-. +W/ 9 .-. +W/ + * + * 9 .-. ++W/ * * + -.&? 06 3 2C6e 4 L10+ C(' )M"* 1 9 + > 5 4 w &+(+,+ zx-M "C('mG,'>+ 73 % ,L.-. -.& ++ ,.W/ :E9Q*. ++ ,.Y/)< $-. W/ ++ $-. +W/ ++ ** $-. +W/ $-. ++W/ ++ ** 9 .-. W/ ** ++ 9 .-. +W/ 9 .-. +W/ ++ 9 .-. ++W/ ** + - . &? 06 3 2C6 ! = )Mu"* 0 9 + > 5 4 w &+(+,+zzx- " = mG,'>+ ,L.-. -.& ,.W/ ,.Y/)< $-. W/ $-. +W/ $-. +W/ $-. ++W/ 9 .-. W/ 9 .-. +W/ 9 .-. +W/ 9 .-. ++W/ + ++ :9Q*. + ++ ** + ** ++ + ** + ** -.&? 06 3 2/%6f! = )Mu"* 0 9 + > 5 4 w &+(+,+ zzx- " = mG,'>+ 74 % + ,L.-. -.& ++ :E9 :E9!Q*. + /)< * ++ * + /)<Y:E $-. W/ ++ $-. +W/ + $-. +W/ ++ $-. ++W/ + + - . &? 06 3 2C6 4 6 2C6e)"* 9 +> 54 w&+(+,+- zx-M "G,'>m2C6e+ D1.&&.-..K QV ,L.-. -.& + + + ,.W/ ** ** ++ !+ ,.Y/)< $-. W/ $-. +W/ $-. +W/ $-. ++W/ + 9 .-. W/ + 9 .-. +W/ + 9 .-. +W/ + 9 .-. ++W/ - . &? 06 3 = 3 !+ L 5l= 3 + 75 % D1.&&L.-.&@JQV + ,L.-. -.& $-. W/ ++ $-. +W/ * !+ ** $-. +W/ $-. ++W/ 9 .-. W/ 9 .-. +W/ + 9 .-. +W/ 9 .-. ++W/ + ** + + - . &? 06 3 = 3 4 L Y+ L 5l= 3 + + D1.&&.-.&,9QV ++ !+ ,L.-. -.& $-. W/ $-. +W/ $-. +W/ + + + $-. ++W/ 9 .-. W/ 9 .-. +W/ 9 .-. +W/ 9 .-. ++W/ + - !. &? 06 3 = 3 4 6+ L 5l= 3 + 76 ' > ? ! == 4 = ; ?5 "< 3 + & ? = 5 = " !- ! ? + " = ;< ? !- 3! A ;[- 3 !? "- ?!-4 -= - ? ? !+ & " !6? ! = ? "! 4 = 5 = 4 - - = ? "!" 3 =+ > = ? ! 9 = " ? ? 5 - = - <= " - D 5? -3 = %/6q - 4 4 )GF M*+ > 5 = 4 ; 3 " ? ! - ; ? ; = = 5 = ),TD 1*- 4" 3 =- ] D ; " - ;k ; ]A ? D- 5 4 )GF M*- 3 = ? ! + % [ - 5 = 4 D <= < ),G* 0695 )T O G " O C96 F 1*+ > ,G 4 < ? A 5 A " 5 " ^- A4- ;[ 5 !+ > 0695 4 ]A 5 A 77 ' " 5 < - ; = " 5 = A" 5" 6 1 )C N 3 *+ > ,G 4 ?;k = 5 < 5 =- 4 9 3 " " < - ; ? - 68" " <- ; !" )L; *+ 3= G22 9 - 5 D H% '= 5 < -3= )C" * ? <= ,G[ 5 ? " -[ = +> 06 - -?A ? - ? D 5 = [- 5 ? [ ! H% '- Z <)/" *+ >? ;? 5 = [ ? ! 4 <= " - 3= 9 )' O C 3" * 5 )( =8 OA=D O'A9D, 1OC" 1O ?? N G- M*+ " )'B* 4 < < " - < " 3 " 5 3!";=3 " 5 )(E* " '6 ? + 'B ? D " ? - ; ;k = >6- 5 9!5 <- 4 - A 5 = G% 4 = 5" ; D )TN7 "-*+'B4 ? 5 !5 5"- [ - < )G= N T YD- 78 ' *+ ! 5 'B ? D " 5 - 4 = 5" "- 5 g ? 5 )''*- ] 4 " 5 )(5*+ '' 4 ? D " )'B*- %G(B- 5 " ) " N - *+ > <= 'B 4 " ;<3 D < )B Y N "- 0*+ '3 ^ ?!" - 'B 4 l 'B ? D ) "N -*+& ^; !56A<"- 9A 'B- -3^5 "5 ? - ;<3 'B ''- ; 5 = )'9 O 3- O B Y- *+ - 5 = " )'Bm''*+ & ; <= 'B [ "? = = 9- ; " ? = )T N T9-1*+> 34? <='B ? D G22)B * 'B ? 5 = = )' *+U ;<= 'B D G22 4 l ; A= ) ?? N G- M*+ I " ? ! - ; " ; 'B ? 4 H !? " )T N T9- 1*+ 4 - 5 = ; 'B D + ( 5- <= 'B 4 <" 4 H9 H9- 4 3 ? 9 )HY *+ 79 ' > 3 ; -06 - ? D -= <= " - 5 G22 D H% ' - ? " +%5 ? [ = - ? D = = ! H% '- - ? D ? D <='B ! = + & ; " [- = <= 'B < 5 < - 5 D H% ' )C" *+ > 5 34 = ? ! = <= 'B [ )A=D 1O G ' 0O DAD O D O > O 'A9D , 1*+ %6 < - 5 D H% '- =9 I = -"; 'B 34? = 5 =? ! ) *+ > 3 ; -06 - ? D 5 = 5 D H% '-= <=,G = <='B+ 4 < - " 4 5 A 9- D !? D 5 )3 N - *- ; 4 "I D!? !?- 3;< ; D ? ? + ,(> = )6* !5 9" A 9 )B>* ; 4 ^ ? ! )C 80 ' *+ & A 4 4 = 5"- 9 = 3 - = Z3 3 6 ;k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g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g" !?-";] = " ), N L 8- 1*+ ,,(6 4 - ; ,,(6 5 = - ?3 )( = *+ & " - ; ,,(6 = ; ? ! - ? " ) M*+ G ? - ,,( G22- ; "? = g = ) 5 *- - ; = 3; = ,,(6 4" 34? ? )( = *+ % ; 3I ?A ? ? D = 3 = ,,(6 ? " + (4- 5 ? [ " = = - 06 - ? D ; = 3 = D 1-l-0-1lM0-0l-= - " + ? "- 3I = 3 = D -0l+ 7 ; 06 = 3 ? D D =D)/" *+ A D"A? ; 9= ? < = ,,(6 " 3 " - 3 3I ?A ? +, )* 34 ;9=? 84 ' < = ,,(6 " 3 <- 5 D 5 ? !)G''*+ 3 ,,(6 34? ? ! -; 3I = ,,(6-]A; )( = *+% - ; 06 - ? D = 3 ,,(6? = ,,(6- ; 4 3 ,,(6 ; 4 A= ]Z - 3 = ,,(6+ = = 06 - ? D = g = 5 - 4 ; = D ,,(6 3I 5 ) " *+ & - 4 ; 5 ,,( 3 H2,( 4 !6? ! - H%/6d 2C6e)'9N3-OC O ' 4 1*- H%/6d ,,( ) O % 0*- ,,(6 !?)9 8 3 1*+ > ? ? )H%/6d* 4 !6? ! - ? D ! !? " = - ? ! )L] 6 " M*+ 3 H%/6d ! ?! H 4 <? - H%/6d = )H&*+ ' H& ? = - H%/6d = ) N L"- *+ c = H%/6d ?^ = !? "- 4 H- 5 4 4 = - !? ? - - = " ? " +>H%/6d 34" = !6? ! 5- 2C61 2C6e 85 ' )' N T - *- A 3 ,,(6 !?- + > H%/6d 4 == " ? ! + > ? 6H%/6 ? D 34? 9=A 5 ? 9! )L] 6 " M*+ " ?A = G223H%/6d-5 - ; " " L% H%/) NL"-*- 4 ?5 3- 6H%/6 ? ;4;= Ml G )L] 6 " M*+ ( - 3I ; = 3 <= H%/6d- 6 4" ? ! + > - D <= H%/6d 5 ? " - 5 [+ > 34 = = ! = ? !+ & = ? ? ! - =I !6? ! G22- D ? 06 + > = <= H%/6d-3 = ,,(6 "+G? - = <= H%/6d = ,,(6+ ( - 06 3 = ,,(6 D <= H%/6d ? g = 5 - 4 ; = D ,,(6 3I 5 ) " *+ & - 06 D <= 2C6e- 34 == 3 ,,()C *+ 86 ' 6e )2C6e* 4 !6? ! D =A 4 !- !? "-!?-4 4 Z)>9 *+2C64= 2C6d 2C6e- ? " 5- 2C6d g3 " 4 - ; ; 2C6e 4 +><= 3 2C64?" " 2C6L )'N'9-*+ c g?^- 2C6e A = =A 4 ? !- 5 4 )( ] *- 3 !5<- ? "" ;A - 4 4 ? ! ?33 < D < )/ N( -*+> ? 2C6e; H%/6d4 ?3D <9A < A ? " ) - 1*+ 3 34 = ^ , 3 ) *+ % G22- <= 2C6e 4 3= 3 9 5 )C"8F *- ; 5 2C6d 2C6e A - 3 2C6e34? " = )' N'9-*+ % ; - 06 D <= 2C6e 5 ? [ - M-1l- M-0l 1M-l- = + 7 ; = = < ? 9 = ? D )/" *+! = 06 = <= 2C6e- 4 ?A ? = <= + 87 ' >? = <= 2C6e- == 3 !+U ; "! " - " ? 3 =<+ & ? 4 3= = =A !- - 3 = 9 )= M*+ & "!- A ? = == = )/ 9 *+ 4 - = 3 3 2C6; = ? - ; ! < 3 = )C"8F *+ c ? ? D 34= <= 2C6e = ! = - 4 = ; D 4 = )'9 /, G -*-45 = G+H =D? ] = g < ? ! == 5 -; 9 G; L$+ 3= 5 D - 06 34 = 3 <= 2C6e & = 3 -l t, 06 = 3 -1l -0l- ^ M t,- = + 3 2C6e ?!5- = Ml 4 L Y-; 5 D + 4 3 2C6e- 06 34 3 2C6-2C62/%6f-= 3l 2/%6f- t,+ 06 = 3 4 L Y- 4 4 - 8 )* ; 88 ' 34 3= = 3 4 - 3I + c g?^ ? !-9A= ; 2/%6f A 3 {"9 ]h ? " !?)( ] *+2C6D ? 4 H-? !-] -3 4 ; D- 345?3 4 )L"N-*+ 2C64 !? "4 -; = !?<= - L$)L"N-*+ 3= - " 4 = 5 - 3 !6? ! 9 " 9 )L *+L 4" ? ! D 3 H%/6d 2C6e-< 2C6;4 ? ! -4 34= )L"N-*+ & " ; 4 H%/6d 2C6e- Z D -; = 06 3 !6? ! -?" G ? - !6 ? ! -H%/6d2C6e-? - ? ! + c I !- ? ! [ A - 4 4 - - ;k !+ > ? ! D H% '- = l ! 3= ! H% ' ), *- A 89 ' ; 4 ;k 3 4 ? = ) *-A< ; 3 ), *+ & - ? < " 9 " 3 ?3= 5 - + c - "- ;3 06 3 " 9 ! ! H% '+ % 5 ? [ - 06 = " 9 ?A ? - " )?" *+ H = "- ! ? !+ > = < ? D = " - ? 3- 9 =? < " )/" *+ 4 4 9 - 3= !- ; ? 3 ] ? ! [ )'A9D , *+ 4 - ! !" ] ; 4 ? - < g 9)C=-0*+% ; 5 ? " - ? D + % - 5 ? [ = - - = 4 ; 3 06 + G? -"! 9 3 D 4 = 9 - = ? ! 90 ' = 3!A" -;k ? ! )' 1*+ & ; 34 9 3 ? = ? ! + > ? = 5 ? ! )L 9YD *- [ ? ; 3 H% '+ ' 06 - " 5 ? [ - ? D [) 3 *+G? I4?< = ? !"- 5 4 = 5 )7] M*-;k- 34 I !5 + G ? - ? < ? 3= I- 4 4 <= 3= ; 3I ? D = 9 A=- ? "; !- ? 5 " + % 5 ? [ - - 9 = ? < - 06 = 3 ! = ? D + ! = ? !- 06 = 3-Ml !0l 5 -; ; ; 3 3 Ml !l 5 -= g3 = ? D )H 3 5*+ 2 4" G22 ; ; " ? 4 ? )T N 7 "- *+ % ? = ; = < Z ? + 91 ' B" - ? ! 4 D ? " Z 4 !?-!?-! !? " I ! + > ? ? ! 4 9 - 3 = - D 5 - - 4 )i N 9 - 0*+ G " - 06 ? ? ! ? " -; 3= ! 0l- = ) 3 5*+% ? [ -06 = !01l- g= ; ? l+ > ? D = ? ? ! " - 39 g 3I +% ! = - 06 = 9 ; I = - = - ? D - ; 3= M-l ! "+ 9 I !- ? ? ! " = <- ? = ? ! 3= 34 3; - /- ,(> <= = + > I = - ? 4 [ + 4 5 " - == 9 + U D = ^ ?!" - ?< 3;< - ; 9 4 - - ? 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F =F ? 9 3F H% '+ . &-=+1M-+1M61M-+ L$V-H+OQC7&V-R+OL&'(>-&+O>&H&-,++OVLV$&C>++&???F 9 "?93D9 ? + . &-=+1-+061-+ $VV>L&- '+O , G>%CG- ,+O ,'`%- &+O G$>- C+O C&(>L&- 7+O />%H2- ,+H+O2>C>-+OH&LL%>7-,+C+O($H2-+(+OHB2&,&L,%%-+H+ 101 %0 3 6 3 ="- 3D ? 6 +$-62.-=+01-+6-+ GC2- $+O CT- ,+O i$&C- G+O $CT&L- +O >7&L- B+O 'iG,- +O 'B2%- + H9? =5F" 3 =+ :7. 81J. &-=+-+-+1610-+ G%&'&- '+O '%'- ,+O /2>B2- + 2? F 3Y . 9 ? = ? +- - 8@J-=+-+0#0-0+ G&C&Lc-+O>&L6L>$''&$-+O7&L%2&L6,''>$2CC&-+O'CC&L>%-R+O CG&- ,+O (>2L2&L- +O C&L& >$L'- &+O G$('- R+C+O ,&LC&- 7+O ,LH2- L+O G$B,&C- +O >LH>H- +O 'C>,&V- R+C+O >C>, &C- R+/+ , " ? ? F 3Y 9 ? . = ??+:7.#J.-+G>2+3++ G&C&7&- C+G+ N T(C>2HV- %+ 9 3 9 5F+2.02-=+M-+6M-+ G&$C/-%+C+'+ : 1& & & & & 7. K L3 (-M+ GB2,%- ,+O &'HLG6/L%>- R++O (%G>- R+,+O L,2L&V6$2CL- /+R+O '(LHH-B+O7Vc$&V6>LV>-'+O(&L&V6,>C2%-+OCC&>'6'%G>7C-L+O ,>L&%>- L+O L- %+R+ 2 F5 =F ? X Y9 9 " h + ,.. & D:-.8-+11#111-+ G2'H'2-C++O,$&'>-G+O%2&H>-+O72C&'-+OVLV$&C>-+OC7&V- R+2 6? F =F?( - ? 9 ? - 9 3D?9 ? +. /&-=+-+M6-0+ G2'H'2-C++O'&2H>-C+%+O>%VC&V-/++O72C&'-+" =F ? ? ( 9 3 + + 2 -. , 7 ) 8 7 /&. . @2- < 06 3- 6& -0-+ GLiG&%- ++O G&2$- 2+O LH&&C- +O ,C2%- +R+ ? 5 = 5 9 F+ ,- 5 .8 @ - =+-+#1-M+ &G&C C$,- T+C+ N H$L%&L- R+L+ H9 "9 ] X F . +3 8Y+,- <2.84=+-+M#- + &G&C C$,-T+C+Oi%-/+Oi,>T-H+O(>CT-G+ +L" ? " 9 9 9+ :7.#J.-=+- +0#00-1+ 102 %0 &%-G+O>hT&%%&Gi-L+O,>L%-&+O>E-G+O(L>''&L-&+OHB>L%&'-L+G+H9 9 "F- 3 F ? 6 +-/ 1@-=-M6M-+ /&$C&%- L+ N L>''&% &T- B+ ,889699 % 9Y % =HFH9F ?398= / 3" = V8 889 ( + ;9)8.] _ 27 7-28.2,24=+M-+#0-0+ /2%- G+ N (CC>%&- /+ 9 9 ? F8 98 2 G~ :7.#J.-=+0-+'-+ />C2%U- +O %$HH&%- '+O 'H&2GC&L- C+O G&%%2%- 7+O >$G&L>$LH- G+O ,&L&%2&L-+O(>H- +L ?2=$?9,H% '6 2 , &= " 6X F ( ? C . H9 ,3" + & )-=+M-+-+#0-1+ />L,2- R+7+ N L&&C'>%- + L=Y ? 9 3"F ? ; 3? =+&9,20N4=+-+16-M+ /L%B2,>%H- G+O C>$2'- &+O G$(>%H- (+O 7L2%GH'6&7&LH- i+O G&&- +O BL>$'>'- +O &&%&%- 7+O &C2B&- R+ G =F ; 9h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c+ ( ? 5 6 6? F+ 6-.7 : 7&,8 ^@2-=+-+#-+ >- c+O ,&2R&L- ,+R++O T$ &%- /+R++,+O '2&L- +/+,+O TL$2G&%2&L- C+O G$2R%- +O &L- ,+O B>&V%G- L++O C,&L'- + +B++O 7&L'(&H- B++ 103 %0 &5 ? 5 6 6 ? Y9? F3Y )2 G*+E-=+-+M06M-M+ L26L&V- +%+O (%- H+>+L+O G&CG>- B+(+O 7&C'c$&V- +O ,LH2%&V67Vc$&V- ,+ 6? F =F ? ? H( +. /&-=+11-+6-+ L-(+O72Ri6T$,L-,+O%-C+O&2LHV-+H+O,&LC2%-G+O'2HL,%- '+7+O , 5 66 ]F = 9 = ?? ? 5 6 " + 6 28. 5 E28.4=+1-+M#0-+.+M ]"+0M0+ 2C &LH- B+/+ , ? 96? 59 "+ & $O8.@. /.#.-=+1-+16-+ 2H%2T- + 2? F 3Y . Y + )& 6 5 .=+-+61-1+ T&- ,+%+O 'B%&2G&L- ,+O &2C- +O ,%%'- ,+(+ G?? " ?? 9 %/6q =F 9 9+ @-. 8 &-=+M-+#0-+ >%_C7&'- ++,+O B&L%%G&'- C+O >C27&2L- %+C+ +O %HC2- ,+L+,+ = 5 ? ! +,,-&)S&4=+-+-+6-+ >%VQC&V- L+O 'Q%B&V G& ,&G2%- /+O QC7&V- R+O L>GL2$&V6 &V'- ,+&+O G$LH&- R+O VLV$&C>- + G F = & 9 " ? 5 ? + : . 6-. <7 D &- @2-=+-+0-+06M-+ L>'B2HV-T+L+NB>%-'+(+2 3 ?., " 9"+ 6-. 7 ..8 & ,.. :-.84 =+0-+-+6-+ BR2,&- ,+O 'B$2B2- i+O ,T>H>- %+O ,'%>L2- i+O 2T$T>- T+O H'$'B2- T+O ,$H'$>- '+O T&22B2- H+ 293F ?? ? 069F 9F F9 Y 9 = ? 9 = +: 6,-=+-+0#-+ BCC2&CC- + N $HH&L2G&- R+,+ >5F" 5F- 5F" - +#26-=+-+60-0 BCC2&CC- + H9 ? 5F" 9 - Y9 ?9= F+; 4=+-+-+61-+ B&C2- H+O BC,&- C+O C((C2%&%- ,+O />G'HG- B+O (7>C6'TT2- (+O H$L$%&%- $+O /LTT2C- ,+O TL$'2$'- H+O T>%H$C- T+ LGM%>G " = Y9 ? F " ? ? 9h +5- 4=+M-+MM#M1-+ 104 %0 B>C,&'- &++O i>%- '+C+O &2V%B,&L- G+O T&'B7LV2%- + 9 ? =?5 = " = =+ &)-=+0-+M-+6M-+ B>$CH- R+L+'+ N (iQ- ,+ (9 " 39 ? . Y9 9 + 5 2.- =+- +0-+6-1+ B$- i+O B&%- E+O G$%- B+O B$- i+O ,$- E+ 9 93 " 93 ? 2C61- 2C6- &6 HE C('6 = 9 + :-2. :- N.- =+- +0- +MM6MMM-+ Bi$%-R++N,i&L-C+,9 F"? F3Y + - 80&8/2-=+-+0-1+ 2%>BL-%+O>$L-i+OB&%-/+/+O,$H>-+O%$%&V-+B %? = 3 F 9 + 6 #. ,2- =+1- +MM# MM0-+ 2'B2BL-'+OV2V-,+,+Oi$T2+H+OTV$,>L2-B+OT2%>'B2H-i+2? F 3Y . =Y ? 9 ? "+ 6 5 .+- =+00- +#-+ 2'B2i,-,+OH>,2%-B+O'B2-,+O'',>H>-T+O>BT$L-i+O$&%>+T+ 3 F ? = 3F = F5F Y9 9"9F Y 6 3 D - F = #.2 #-..+- =+- +M6M-1+ 2,>H>- ,+O T>R2- H+O ,T2i,- T+O T> i'B2- %+O %T%&- (+T+ ? F 9 = + 6-. 7 2.8- =+- +M6 M-1+ R$LR$'-+L+OTB>$Li-%+%+OL&2,$%G-R+,+ ?? F3Y +62.0N./ 2&4=+M-+6-0+ T%&T>- H+O HBL- '+O HT i'B2- /+ '! ? 9F56 5 = " G% 3F + #. 2 #-..- =+1- +0600-+ TLC''>%- +O TBC/%- C+O GBCL&%- +O 'H2 L%G- H+O />CC2%- (+ %9 8 99 =F 3 ? Y9 " F = 3 + :7 &:- 8-=+1-+-+#1-M+ TL(-'+,+NT>B- H+L+>5 = 5 X F3Y +/-=+M-+6-1+ T2,- '+B+O T%- T++O VB%- L+O (2>- ,+R+O T>- G+>+O %- V+B+O B&- '++O T%- '+'+O C&&- T+B+O T%- B+T+O T%- B++O Bi$%- R++ (= 105 %0 ?? ? " 5 = 6 " = ="" =5F"+ 2.-=+-+-+61-+ T>T-'+B+Oi&B-++OB&%-,+C+OT$>-,+i+(+&9 HL2C6 9"9GLM " 9 '' + <. <.4 )*.+1]+ "F+++ T>$HL>$ T2'- 2+&+O ,CC2LT2- %+O G2,>$C2>'- (+G+O TL,2L2'- T+O 'H%'- &+O T>$L>$,C2'- &++ G 5 F Y9 ? F 3Y + & )-=+0-+-+0#0-0+ TL2'V-R+&+O'BL>%-(+O'H&%'>%-+/+c = F? ? 3 F5 =F+?? 9 9 +5 .8--=+-+006M-0+ TL$2G&%2&L-C+N7&L'(&H-B++5 =. 9 ? F3Y ~ /& 7:7. - =+-+M#1-+ TL$2G&%2&L- C+ N 7&L'(&H- B++ L=Y . 5 = 9" ? X F 3Y ~ . 2.02-=+1-+#M-+ TL$2G&%2&L- C+O T$2(&L- 2+O C,&L'- + +B++O 7&L'(&H- B++O 2 5 = " X F 3Y . 6; - D - Y9 5 + 6-. 7 2.8- =+- +# 1-+ T$'H&L- L+,+ N L>B- C+,+ - 5 + 2 '2,b&'- +,+>+- 'B&%T&C- >',%%- +- ,&CC>- R++(+- ,&%HV- C++- (&HL>72T- (+L+ )>"+* &. & 4++=+#(" / !.&+$= / L '-+0M601-+ CTH>'-(+C+O/2'B&L-'+OCTH>'-C+OC-2+O(((R+9 9" ? X F 3Y 6 8 3Y " 3 ? . ( 9" 3 3 " 9 " "F 8 JK ~ 3.& 6 5 .+- =+- +- +60- 1+ C$H&L $L- +B+O 2CV&L- ,+O L>&GG&L- &+O 2%$&%- + G " 9? +3?9F9 = 3F M6 F + 2 , G&L,>HH )&+*+ :7. 8 1J. & - - & 7- - 2 . &= '-+6-+ C&$%-T+%+OC&$%- (+i+OT>%- C+(+OC&$%(+T+ 2 F?? ? )1-69F5F * F9F 9 "+/.:-.+-=+-+6-M+ C&72%&- +G+ . ? ? F :7. 8#J.-=+1-+-+6M-+ 3Y + 106 %0 C&72%&- G+'+ ? ? 9h + 2. HL%- '+L+- 'B%B%-/++-0601- N8- -0+ C2$,'Ti-,+O'2,>%-(+C+OTL,&C2-/+OLB,2C&2HV-G+L?8 ? F 3Y 6 9 " = + 5- - =+-+1161-+ C2B6 L>Gi-C+O (>&CC-'+L+O >CC2&L-T+(+OL&GGi- +,+O&LB2-L+OTB%- &+O&2'',%-+OTHV'+O/C>iG-L++O,T2%C&i-,+R+O/2'B&L-'+&+O,$CC2%- +&+ 2 5 = 5 ? ? ? F3Y +)-=+0-+61-1+ C2,- &+'+ N GCC- G+'+(+ (5 < . = 3!" + #O.6-.72- . )+-=+-+- + C2%- B++O H'2- '+B+O B&%- +'+O B%- i++O C&&- +,+O C2- V+i+O C2%- +,+ '# =F 9 ? = = 5 9 5 6 93" ? 6 ="" =+ #2. 2.8- =+M-+01#0M-+ C2%-+C+O%-+R+OH'2-i+i+OC2$-+C+OB%-R+,+OH'&%-H+B+293F ?? ? 5 = " 3F 63F 9F5 =+20N.-=+0-+0160-+ C2%L&'- 7+O C>%'>- 7+O C 2%- ,+C+O &CCU'- ,+O 'Q%B&V- G+R+ C 5 5 8F = ? Y9 ? D+0N.8-=+M1-+M#M1-+ C>/H$'- &+7+R+ "F ? X F 3Y . - = - = X+ 5 .8-- =+1- +M0# M-0+ C>%- L+/++ N Ti- +L+ > - 8" ? F 3Y ?" 9 F " ? " F+: 6$&.-=+-+M#-+ C>$&L2>-+OGhL&%2>-+OG&CC&7&-,+O>'&%V-7+OG&CC7CC&-%+O ,VV- +O G&C 7&B2> C%>- + 9 = 5 = " 5 + & E +- =+M- +1M#10-+ C>$&L2>-+OGhL&%2>-+OG&CC&7&-,+O>'&%V-7+OG&CC7CC&-%+O ,VV-+OG&C7&B2> C%>-+G=? 5 = " 9 9 ? 5 + )- =+ 0. 0#-1+ C>L2- 7+O GH>- 2+O LV2%2- /+O 2'$2- C+,+ ,F5 . Y 3 8 ? X 9 9 F F+/& 7:[ -.+MMM1M-+ 107 %0 C>$2'-&+OL2 &%'-+O>G>%-+O/L%B2,>%H-G+OL>>H&-G+OBLGi-%+O >%27&L- R+O &C2B&- R+O ,C2'&- ,+ 2 ? 5 6 93? 63F? ? F3Y +,.$N:-.-=+-+0601-+ C$B2%2- ++O L>GL2$&'6>L'2- (+O &'HL2- '+B+O '&2H>- C+%+O 2H2&%2'- +O (&CC2VV>%- +B+O G2 'H'2- C++ 2 6? F =F ? 069F5F 93D9 ? +#.2#-..-=+-+-+06M-+ , C2LR%- $+O G2%G- +T+O 'BL,- '+T+O B>'B- + & L ,9 GF? L " 9 / &5 ,,+6:-.+-=+-+M61-+ ,G'&%-T+O>L%2'B-+O'>(&L-(+O,T2%&i-+OR2R>%-B+OiB2,&-+O G>iC&- R+O R&&CC- C+O G& '2,>%&- + (3 3 9 9 9 3 ?+5 .8--=+-+M#M- + ,LH2%2- ++ N L%G&'- R++ 2 ? ? 39F Y99h +I.32+-=+M0-+16-1+ ,LE-R+BY9"F+ )-=+-+6- M+ ,G'C&i- R+&+ N L,(H>%- G+'+ (F9" 2 G. Y "9 9" 9 +5- +-=+M0-+060-M+ ,i&L-C+&==" "9 9"?2 G+ 65 .+-=+0M- +61-+ ,T&%V2&- '+R+O T&L- ,+'+O $/2%H>%- +G+O G>&- +/+ &= ? >5 6 2]F &9 " 2X F Y G + 6 ,. : -=+-+1#0-1+ ,&G2%- + N LG>,'T2- ,++ L ? 5 ? +026-.<72.8&$N .02- - =+-+#-1+ ,&G2%- +O 72G&C- '+O LG>,'T2- +O LG>,'T2- ,++O %H>C2- %+,+O $L%&L-/+O72C'&-R+O'C'-+O,C&CG-R+L+ 2 =F 5 ? 5 6 ? + 6 28.5 E28.-=+0-+1#-+ ,2GGC&H>%- &+ N T%G',2- + :( ? = ? ? F?:2.;-- 9,20 +- =+-% 2"F-G+,+T?+-+611-((-%Y i8-+ 108 %0 ,>LL2'- +(+O &T- (+C+O B&LL2G& +O G&(&- +O 'V&V$T- ,+L+O CC&-R+C+B ?9? 9 +5 .8--=+1-+M6-+ ,>LL2'>%- +O B&G>%- +O 2 '>%- (+ $ ? F 3Y + - ..8284=+-+-+ ,>H- +,+ 3 ? F "+ -@J4:-.8`=+-+60-+ %7LL>- /+ N B%$&L- '+ + H ? 2X F Y G . ' ?F H 3F2+026-.75 .84=+-+- + %&&- C+&+O ,,>LL>- H+O ,( &CC- &+O 'CHH&Li- +O Li%- ,+(+ H%/6d 2C6e# " ? ,,(6 H2,(6 5 3 + I&8: .-=+11-+1#1-0+ %&$,%-,++2F?? F3Y + 0. . @24=+0-+#1-+ %2&C'&%- +B+ N L'T6,G'&%- R+ , ? ? 9 ? F 3Y + )& 6 5 .4 =+- +1- +06M- 1+ >&H&-,++OC7&V-R+OL&'(>-,+&+OL$V-H+O>%VC&V-,+OH>LL&'-,+2+O VLV$&C>- + &?? ? 5 ? + 2.8--=+M-+16-+ >$L- i+O >%&%- G+T+O 2%>BL- %+O %2>C&- G+C+O B&%- /+/+O L,>'- L+O L2HH>%-B+O,>L%-H+OTLC2$'T'-L+OG$&LL-L+B+OBTL-R+(+O L%H- '+L+O iC&''-H+,+OT2L'B%&L- +'+O B%$&L-'+ +O%$%&V- +O B>-R+B+ ? 9? %>G Y9 3F 9h + -+-=+0-+1#11-+ >B,- H+O B>L2- ,+O 'H>- T+O >VT2- B+O TLT2- B+ 9 Y9 86e 3F " 9 = ? 6 F6 9 + 02 6-. 7 #.. ,2 8- =+-+0-+00#00-+ >TG-i+O,2i$B2-%+O'$V$T2-T+OT> i'B2-H+OH'$H'$2-+O,i$V$,2- T+O %2'B2 &- '+O >T$i,- H+ 293F ?? ? ? = = 3= 33 """ + ,2 2 #-..-=+0-+M6-M+ >j,>L2% -O H> 2% +O '$V$T2 i+O >jL2>LG% H+ L8 ? ? F 3Y +)&65 .)-.4=+-+M61-+ >HH- '+R+O ,$'/&CGH- ,+O &%G&L>HB- G+/+O B,(&- R+O L%H- >+O /C'B- $+L+O H2,,2'- T+%+O 'BL&2 &L- '+ L =F ? 9 109 %0 3 ? Y9 =? F3Y + 5- +-=+M-+1M#1-0+ (CC72- +O 72Ri6T$,L- ,+O %- C+O &2LHV- +H+O ,&LC2%- G+O '2HL,%- '++ , 5 66 ]F = 9 = ?? ? 5 6 " + 6 28. 5 E28.4=+1-+M#0-+ (%- '+C+O B$%- i++O $B- R+B+O B%- i+C+O (&%- +i+O H&%- +,+ &93L 6 ? = ?Y" " F + #2. 2.8- =+1M- +#M- + (%R- +O >CG &L- '+O &T,%%- C+O TL2'B&%- (+O ,i&L- C+ H9 " ? ; ? ? F F8 3" 9 9 + 02 6-. 7 :-.8 =+1- +1M#10- + ((GT2'- T++ N HL%- '+L+ 9 9 ? ? F 3Y + 5 .8 . 7 2 - =+- +- +6 1- (LG>- ,+(+ 2? ! F ? ? . F +0&- &-$= -1+ (LT-+OR2%-+i+OT>%-B+R+OB%-B+R+OT2,-+i+OB>2-+OT>%-H+T+O T2,- ++O T2,- +R+O B>2- i+B+ 2 ? 3F 9 8 $ . L ? 6 5 6" 8 " "+ 0N. -.+1]+=+++-+ (LT'- ++O 2C'>%- +C+O C`(&V6 >G>- i+'+ , 5 ? ? F+ - @J4 :-.8-=+0-+1-+161-0+ (7C2T- T+(+O CL>$E- /+'+O /$'&C&L- R+O >C/- L+&+O Li- C+O B>//,%- R+O L2'B,- ,+ + L ? = 3 ? 5F" " ? F 3Y + @&. #.8 & /&- =+- +- +6-+ (iQ-,+OBCC2&CC- +OB>$CH-R+L+'+2 ? ? 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F F8 9j = + $-6-.7,..: +-=+-'-+0M6M-+ L&c$&%- R+L+O /$- ,+E+O B,&G- ,+$+O R&%T2%'- +R+O Ci>%'- H+R+O i%&'- R++O HB>L(&- '+L+ c ? 9F 069F5F F = 5D 9 Y6F + #26-=+-+6M-+ L&V2&- +O (LT&L- L+G+O G>CCB2- ,+ >5 = ' ( 9" ? 2X F YG .&99 ~ )4=+M- +M#-+ L27&2L>-,+&+OG&T2,(&-%+O,>C2>%2-+O7QVc$&V-L+O,>%V>L-/+O'Bi> +O G72>- + . > Y9 %= (" H9 (=+,- /&.,2 84=+-+-+M6-+ L>GL2$&V6 &V'- ,+&+O C7&V- R+O C>L&%H&- ,+G+O >%B- +O ,$&'>- G+O VV>$V- '+O >'$%- +O L&G>%G>- C+O VLV$&C>- + G F 3 Y6" ? 9 5 3D? 6 + 6 - 4 =+- +1#-+ L>&''%&L- +O T$&'H&L- G+O ,C/&LHB&2%&L- (+O 'B%&2G&L6'H>T- L+ >5 = = 6 "+ 2.8 a @2& 4=+0-+M#M0-+ 111 %0 L>C&L- + N %G$'- H+ F8 2? F Y G + 3.& 6 )-4=+-+#-+ L>C&L- + = = ?? ? " ? " 2 G+ # Z @2 ,.. 5 .84 =+0- +M#1M- + L>R'6LH&%-+O/C>L&'-2+O((C&iLG-+ +L?? ? +,8 ^-=+-+M6-M+ L$&,,&C&- /+,+O '&2G,%- &++O C&%HV&- ,+R+ L" ? 9 9 9" ? ? 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