Computational Enzyme Design

(1)

Computational Enzyme Design

Thesis by

Bernardo Sosa Padilla Araujo

In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy

CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California

2014

(2)

!!

! 2014

(3)

!!!

!"#$%&'$( (

"#$%&'('!#)(*+ %,#'-!)+ .-/!0)+ 1"234+ !/+ '5-+ (&'#$('-.+ !.-)'!6!7('!#)+ #6+ ($!)#+ (7!.+ /-8&-)7-/+'5('+9!**+6#*.+!)'#+(+/%-7!6!-.+'5,--:.!$-)/!#)(*+/',&7'&,-;+<5!/+$-'5#.+5(/+ -$-,0-.+ (/+ (+ %,#$!/!)0+ '##*+ 6#,+ -)0!)--,!)0+ -)=>$-/;+ ?)+ '5!/+ '5-/!/@+ ?+ .-/7,!A-+ $>+ -66#,'/+('+!$%,#B!)0+().+(%%*>!)0+"23+$-'5#./+'#+'5-+.-/!0)+#6+-)=>$-/;++

"5(%'-,+??+.-/7,!A-/+'5-+.-B-*#%$-)'+().+A-)75$(,C+,-/&*'/+6#,+(+$#*-7&*(,+ .>)($!7/+1D34+%,#'#7#*+'#+%,-/7,--)+-)=>$-+.-/!0)/;+E-/&*'/+!).!7('-+'5('+'5-+D3+ %,#'#7#*+ !/+ /&77-//6&*+ !)+ /7,--)!)0+ -)=>$-/+ 6#,+ -)=>$('!7+ (7'!B!'>;+ <5-+ %,#'#7#*+ !/+ 0-)-,(*@+,-%,#.&7!A*-@+().+-F7-*/+('+.!/7(,.!)0+6(*/-+%#/!'!B-+.-/!0)/+95!*-+%,-.!7'!)0+ '5-+$#/'+(7'!B-+-)=>$-/+7#,,-7'*>;++

"#)6#,$('!#)(*+75()0-/+(,-+%(,'+#6+'5-+,-%-,'#!,-+'5('+)('&,(*+-)=>$-/+&/-+'#+ 7('(*>=-+,-(7'!#)/;+"5(%'-,+???+7#$%,!/-/+'5-+7#$%&'('!#)(*+.-/!0)+().+-F%-,!$-)'(*+ 75(,(7'-,!=('!#)+#6+',!#/-%5#/%5('-+!/#$-,(/-+1<?D4@+(+$#.-*+-)=>$-+6#,+'5-+/'&.>+#6+ 7('(*>'!7+(7'!B!'>+!)+'5-+7#)'-F'+#6+7#)6#,$('!#)(*+75()0-/;+G/!)0+(+)#B-*+$&*'!:/'('-+ .-/!0)+1DH34+$-'5#.+'5('+7()+7#)/!.-,+$&*'!%*-+/'('-/+!)+(+/!)0*-+%,#'-!)+/-8&-)7-+ #%'!$!=('!#)+7(*7&*('!#)@+9-+.-/!0)-.+'5-+6*-F!A*-+5!)0-/+!)+<?DI/+(7'!B-+/!'-+*##%;++

J+7-)',(*+75(**-)0-+!)+'5-+"23+6!-*.+!/+'5-+,-*!(A*-+-)0!)--,!)0+#6+()+-)=>$-+6#,+ ()>+.-/!,-.+,-(7'!#);+?)+"5(%'-,+?K@+?+.-/7,!A-+'5-+7#)7-%'&(*!=('!#)+().+(%%*!7('!#)+#6+ (+ 5!05:'5,#&05%&'+ 7#$%&'('!#)(*+ 6,($-9#,C+ 6#,+ '5-+!"# $%&%+ .-/!0)+ #6+ -)=>$('!7+ (7'!B!'>+!)'#+!)-,'+/7(66#*./;+<?D+!/+&/-.+(/+(+$#.-*+/>/'-$;+

(4)

!B

)!*+,(-.(/-0),0)1( (

!"#$%&'$( !!!( ( ( ( (

)&"23(45(/46$36$#(( !B(

)&"23#(&67(.89:%3#( B(

!""%3;8&$846#( (B!!!(

/<&=$3%#( (

(

"5(%'-,+?(((((((((((((((++?)',#.&7'!#)( (L(

( ( (

"5(%'-,+??((((((((((((((((?)+H!*!7#+H7,--)!)0+#6+M)=>$('!7+J7'!B!'>N+J+D#*-7&*(,(( (LO( ((((((((((((((((((((((((((((((((((((3>)($!7/+J%%,#(75+

( (

"5(%'-,+???(((((((((((((("#$%&'('!#)(*+3-/!0)@+D#*-7&*(,+3>)($!7/+H7,--)!)0@+().+ +PQ+ +++++++++++++++++++++++++++++++++++MF%-,!$-)'(*+"5(,(7'-,!=('!#)+#6+R*-F!A*-+S!)0-/+!)++

+++++++++++++++++++++++++++++++++++<,!#/-%5#/%5('-+?/#$-,(/-( (

"5(%'-,+?K((((((((((((((J+S!05:<5,#&05%&'+"#$%&'('!#)(*+R,($-9#,C+6#,+'"#(%&%++ ++TU+ +++++++++++++++++++++++++++++++++++M)=>$-+3-/!0)+().+!'/+J%%*!7('!#)+<#9(,./+'5-+3-/!0)+#6++

(5)

B

)!*+,1(!0>(.?@AB,1( +

R!0&,-+L:L;+ )$#*+,+-%+%,-:/7,--)!)0+#6+-)=>$('!7+(7'!B!'>+(%%*!-.+!)+'5-+

7#$%&'('!#)(*+%,#'-!)+.-/!0)+6,($-9#,C+ V+

R!0&,-+L:W;+ <,!#/-%5#/%5('-+!/#$-,(/-+(/+(+%(,(.!0$+6#,+7#)6#,$('!#)(*+

+ 75()0-/+!)+-)=>$('!7+7('(*>/!/+ T+

R!0&,-+L:X;+ H75-$-+/5#9!)0+'5-+5!05:'5,#&05%&'+7#$%&'('!#)(*+9#,C6*#9+

+ 6#,+.-/!0)!)0+-)=>$-/+!)'#+!)-,'+/7(66#*./+ LQ+

<(A*-+W:L;+ "#$%(,!/#)+#6+-F%-,!$-)'(*+,-/&*'/+9!'5+D3+%,-.!7'!#)/++

+ 6#,+'5-+V+YM+.-/!0)/+!)+'5-+',(!)!)0+/-'+ XQ+

<(A*-+W:W;+ H&$$(,>+#6+'5-+D3+,-/&*'/+6#,+'5-+YM+.-/!0)/+,-%#,'-.+A>+

EZ'5*!/A-,0-,+".#/,;+ XL+

<(A*-+W:X;+++++++++2,#'#7#*+X+,-/&*'/+6#,+'5-+Y-$%+-*!$!)(/-/+A>+EZ'5*!/A-,0-,+".#/,;+ XW+ <(A*-+W:O;+ 2,#'#7#*+X+,-/&*'/+6#,+01#2%,++75#,!/$('-+$&'(/-+().+!'/+LLO+/!)0*-+

$&'()'/+,-%#,'-.+A>+[(//!*(+".#/,1+ XO+

R!0&,-+W:L;+++++++Y-$%+-*!$!)('!#)+ XV+

R!0&,-+W:W;+ D3+%,#'#7#*/+ XT+

R!0&,-+W:X;+ 2,#'#7#*/+X+().+O+-F7-*+('+.!/7(,.!)0+6(*/-:%#/!'!B-+.-/!0)/+ OQ+ R!0&,-+W:O;+ "*(!/-)+,-(,,()0-$-)'+#6+75#,!/$('-+A>+75#,!/$('-+$&'(/-+ OL+

R!0&,-+W:P;+ 3!:(F!(*+7#)6#,$('!#)+#6+75#,!/$('-+ OW+

R!0&,-+W:U;+ <,()/6-,(A!*!'>+'#+()#'5-,+,-(7'!#)N+MF($%*-/+#6+D3+/!$&*('!#)/++

+ ,-/&*'/+6#,+\<+().+!'/+!)(7'!B-+3OV?+B(,!()';+ OX+

R!0&,-+W:];+ <,()/6-,(A!*!'>+'#+()#'5-,+,-(7'!#)N+D3+/!$&*('!#)+,-/&*'/+ OO+

R!0&,-+W:V;+ "#$%&'('!#)(*+%-,6#,$()7-+ OP+

<(A*-+X:L;+ D&*'!%*-+/-8&-)7-+(*!0)$-)'+#6+)('&,(*+<?D/I+*##%+U+ ]Q+

<(A*-+X:W;+ )$#&+&%+7#$%*-$-)'('!#)+(//(>+,-/&*'/+ ]X+

(6)

B!

<(A*-+X:P;+ H&$$(,>+#6+-F%-,!$-)'(*+75(,(7'-,!=('!#)+#6+-B-)+*!A,(,>+ ]U+ <(A*-+X:U;+ H&$$(,>+#6+-F%-,!$-)'(*+75(,(7'-,!=('!#)+#6+#%-)+A!(/-.+*!A,(,>+ ]]+ <(A*-+X:];+ H&$$(,>+#6+-F%-,!$-)'(*+75(,(7'-,!=('!#)+#6+#%-)+*!A,(,>+ ]V+

<(A*-+X:V;+ H&$$(,>+#6+'5-+$#/'+(7'!B-+$&'()'/+ ]T+

<(A*-+X:T;+ "#$%(,!/#)+#6+D3+,-/&*'/+9!'5+"23+,-/&*'/+ VQ+

R!0&,-+X:L;+ <,!#/-%5#/%5('-+!/#$-,(/-+(/+(+$#.-*+/>/'-$+6#,+7#)6#,$('!#)(*+

75()0-/+!)+-)=>$('!7+7('(*>/!/+ VL+

R!0&,-+X:W;+ H&$$(,>+#6+'5-+7#$%&'('!#)(**>+.-/!0)-.+<?D+5!)0-+*!A,(,!-/+ VX+ R!0&,-+X:X;+ ?)+B!B#+7#$%*-$-)'('!#)+(//(>+,-/&*'/+6#,+'5-+.-/!0)-.+*!A,(,!-/+ VO+ R!0&,-+X:O;+ ?)+B!',#+(7'!B!'>+(//(>+,-/&*'/+6#,+-(75+#6+'5-+*!A,(,!-/+ VP+ R!0&,-+X:P;+ <5-,$#6*&#,+(//(>+/5#9-.+'5('+(**+$&'()'/+-F5!A!'+9!*.:'>%-:*!C-+

'5-,$(*+/'(A!*!'>+ VU+

R!0&,-+X:U;+ K(,>!)0+'5-+7#)',!A&'!#)+#6+'5-+#%-)+().+'5-+7*#/-.+/'('-/+!)+'5-+

+ +DH3+7(*7&*('!#)+ V]+

R!0&,-+X:];+ "#$%(,!/#)+#6+$#,-+7*#/-.+A!(/-.+<?D+5!)0-+*!A,(,!-/++

+ 9!'5+'5-+DHJ+().+'5-+#,!0!)(+7#/-.+().+7#/-.+A!(/-.+!A,(,!-/+ VV+

R!0&,-+X:V;+ D3+()(*>/!/+#6+<?D+5!)0-+$&'()'/+ VT+

R!0&,-+X:T;+ H3H:2J^M+()(*>/!/+#6+-)=>$-+/($%*-/+ TQ+

<(A*-+O:L;+ ^-#$-',!7+7#)/',(!)'+7#)'(7'/+A-'9--)+'5-+7('(*>'!7+,-/!.&-/+

+ ().+3SJ2+!)+'5-+(7'!B-+/!'-+/-(,75+().+,-%(7C!)0+7(*7&*('!#)/+ LLV+

<(A*-+O:W;+ MF%-,!$-)'(*+75(,(7'-,!=('!#)+#6+.-/!0)/+#)+'5-+6!B-+)#B-*+/7(66#*./+LLT+ <(A*-+O:X;+ <#%+LQ+.-/!0)/+#)+/7(66#*.+L_M`+1>-(/'+<?D4N+$#*-7&*(,+.>)($!7/+

(7)

B!!

R!0&,-+O:L;+ <,!#/-%5#/%5('-+!/#$-,(/-+1<?D4+(/+(+$#.-*+/>/'-$+6#,+-)=>$-+ ++

+ 7('(*>/!/+ LWU+

R!0&,-+O:W;+ S!05:'5,#&05%&'+7#$%&'('!#)(*+9#,C6*#9+6#,+-)=>$-+.-/!0)+ LW]+ R!0&,-+O:X;+ H&$$(,>+#6+'5-+6!B-+!)-,'+/7(66#*./+'5('+%(//-.+(**+'5-++

+ 7#$%&'('!#)(*+/'-%/+ LWV+

R!0&,-+O:O;+ )$#&+.3%+(7'!B!'>+$-(/&,-$-)'/+#6+.-/!0)/+ LWT+

R!0&,-+O:P;+ MF($%*-+#6+7!,7&*(,+.!75,#!/$+$-(/&,-$-)'/+ LXQ+

R!0&,-+O:U;+ J7'!B-+/!'-+#6+>-(/'+<?D+123b+?3N+L_M`4+ LXL+

R!0&,-+O:];+ H-7#).:0-)-,('!#)+.-/!0)/+#)+(+'5-,$#%5!*!7+/7(66#*.+ LXW+

R!0&,-+O:V;+ H-7#).:0-)-,('!#)+.-/!0)/+#)+(+/7(66#*.+95-,-+'5-+.-/!0)-.++ + 7('(*>'!7+5!/'!.!)-+*!-/+('+'5-+%#/!'!B-+-).+#6+(+/5#,'+(*%5(+

+ 5-*!F@+,-/-$A*!)0+(+7#)/-,B-.+6-('&,-+#6+)('&,(*+<?D/+ LXX+

R!0&,-+O:T;+ H-*-7'-.+.-/!0)/+#)+/7(66#*.+LJPX+(,-+/'(A*-+ LXO+

R!0&,-+O:LQ;+ H-*-7'-.+.-/!0)/+#)+/7(66#*.+LJPX+-*&'-+6,#$+HM"+7#*&$)+

+ +9!'5+'5-+-F%-7'-.+8&('-,)(,>+/',&7'&,-+ LXP+

R!0&,-+O:LL;+ 3SJ2+('#$+)($-/+ LXU+

(8)

B!!!

!**B,C?!)?-01( +

JJ+ ($!)#+(7!.+

"J+ 7('(*>'!7+()'!A#.!-/+ "3+ 7!,7&*(,+.!75,#!/$+

"D+ 75#,!/$('-+$&'(/-+

"23+ 7#$%&'('!#)(*+%,#'-!)+.-/!0)+ "2G+ 7-)',(*+%,#7-//!)0+&)!'+

.:^J2+ .:0*>7-,(*.-5>.-:X:%5#/%5('-+

3"+ .-0-)-,('-+7#.#)+

3SJ2+ .!5>.,#F>(7-'#)-+%5#/%5('-+

01#-%,+# 0*-4"3+-4+/#-%,+#

0-,%*"!++ -)-,0>+#6+'5-+7*#/-.+/'('-++ M3<J+ -'5>*-)-.!($!)-'-',((7-'!7+(7!.+ 0%5"$+ -)-,0>+#6+'5-+#%-)+/'('-++

0.%./,+ '#'(*+-)-,0>++

MKb+ -$%!,!7(*+B(*-)7-+A#).+

6/+ 6-$'#/-7#)./+

^23S+ ":0*>7-,#*%5#/%5('-+.-5>.,#0-)(/-+

^2G+ 0,(%5!7/+%,#7-//!)0+&)!'+

6-/.+ 7('(*>'!7+7#)/'()'++

YM+ Y-$%+-*!$!)('!#)+

YD+ D!75(-*!/+7#)/'()'+

D3+ $#*-7&*(,+.>)($!7/+

(9)

!F

DH3+ $&*'!:/'('-+.-/!0)+

_J+ )#'+(%%*!7(A*-+

_J3S+ ,-.&7-.+)!7#'!)($!.-+(.-)!)-+.!)&7*-#'!.-+

_bc+ P:)!',#A-)=#F!=#*-+

_3+ )#'+.-'-,$!)-.+

_DE+ )&7*-(,+$(0)-'!7+,-/#)()7-+

_2K+ )-0('!B-+%,-.!7'!B-+B(*&-+

_2<+ 7#)/'()'+)&$A-,+#6+%(,'!7*-/@+%,-//&,-@+().+'-$%-,('&,-+

)/+ )()#/-7#)./+

2b"+ %-,!#.!7+A#&).(,>+7#).!'!#)/+

23b+ %,#'-!)+.('(+A()C+

2DM+ 2(,'!7*-+$-/5+M9(*.+

22K+ %#/!'!B-+%,-.!7'!B-+B(*&-+

%/+ %!7#/-7#)./+

EMH2+ ,-/',(!)-.+-*-7',#/'('!7+%#'-)'!(*+

ERG+ ,-*('!B-+6*#,-/7-)7-+&)!'/+

H3H:2J^M+ /#.!&$+.#.-7>*+/&*6('-+%#*>(7,>*($!.-+0-*+-*-7',#%5#,-/!/+ HM"+ /!=-:-F7*&/!#)+75,#$('#0,(%5>+

HH3+ /!)0*-:/'('-+.-/!0)+

<MJ+ ',!-'5()#*($!)-+

<MK+ '#A(77#+-'75+B!,&/+

<?D+ ',!#/-%5#/%5('-+!/#$-,(/-+

<$+ $!.%#!)'+#6+'5-,$(*+.-)('&,('!#)+7&,B-+

<H+ ',()/!'!#)+/'('-+

(10)

F

K(6'-,+ ,-(7'!#)+,('-+(6'-,+/($%*-+(..!'!#)+

KA-6#,-+ ,-(7'!#)+,('-+A-6#,-+/($%*-+(..!'!#)+

KD3+ B!/&(*+$#*-7&*(,+.>)($!7/+

K#A/+ #A/-,B-.+,-(7'!#)+,('-+

7+ 9-!05'!)0+7#-66!7!-)'+!)+(+$&*'!:/'('-+.-/!0)+7(*7&*('!#)+

\<+ 9!*.+'>%-+

(11)

! "!

!

#$%&'()!*!

!

*+'),-./'0,+!!

(12)

! 1!

!"#$%&'()*&(+,-./$(!00,1,&"2(3424/$'2'(

203(!%4!5(!6+,5!0'!5,.7-!+,'!8(!&,44087(!50'$,.'!'$(!(904'(+/(!,3!(+:;<(4=!>+:;<(4! %//(7()%'(!'$(!)%'(!,3!80,7,?0/%7!)(%/'0,+4@!5$0/$!5,.7-!,'$()504(!+,'!&),/((-!3%4'! (+,.?$! ',! 4.4'%0+! 703(="_{! A$(;! %)(! )(4&,+4087(! 3,)! <,4'! ,3! '$(! /$(<0/%7!} ')%+43,)<%'0,+4! '$%'! ,//.)! 50'$0+! %! /(77=! BCD! )(&70/%'0,+@! &$,',4;+'$(404@! %+-! ?7;/,7;404! %)(! 4,<(! ,3! '$(! 0++.<()%87(! (9%<&7(4! ,3! '$(! &),/(44(4! '$%'! 0+E,7E(! (+:;<(4=! D7'$,.?$! '$(! ,)0?0+! ,3! '$(! /%'%7;'0/! &,5()! ,3! (+:;<(4! 04! +,'! 5(77! .+-()4',,-!%+-!04!4'077!%!',&0/!,3!-(8%'(@!(+:;<(4!5,)6!8;!7,5()0+?!'$(!%/'0E%'0,+! (+()?;!,3!'$(!)(%/'0,+=1F!G_!

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{!D!&)0,)0@!'$(4(!&),&()'0(4!<%6(!(+:;<(4!&)(3()%87(!} ',!,'$()!';&(4!,3!/%'%7;4'4!3,)!%!8),%-!)%+?(!,3!%&&70/%'0,+4=!!

(13)

! G!

35%67242,5"4/(8&',-"(50(!"#$%&'(

#,<&.'%'0,+%7! &),'(0+! -(40?+! Q#RBS! 04! '$(! %.',<%'(-! 0-(+'030/%'0,+! ,3! %<0+,! %/0-! 4(T.(+/(4!'$%'!5077!3,7-!0+',!%!4&(/030/!'$)((I-0<(+40,+%7!4')./'.)(=U_{!#RB!<('$,-4!} $%E(! 8((+! (9'(+40E(7;! .4(-! 3,)! '$(! -(40?+! ,3! &),'(0+4! 3,)! 0<&),E(-! 4'%8070';@! 4,7.8070';@! &),'(0+I&),'(0+! 80+-0+?@! +,E(7! 4/%33,7-4@! ('/=VIW_{! X(/(+'! 4.//(44(4! 0+!} -(40?+0+?! +,E(7! (+:;<(4! $%E(! &),<&'(-! /,+40-()%87(! 0+'()(4'! 0+! '$(! 30(7-="YI"O_{! A,!} -%'(@! -(40?+()! (+:;<(4! $%E(! ,.'&()3,)<(-! &)(E0,.47;! )(&,)'(-! /%'%7;'0/! %+'08,-0(4="U_{! A$(! %/'0E0'0(4! ,3!}_{!"# $%&%! -(40?+(-! (+:;<(4! %)(! ';&0/%77;! 7,5()! '$%+!} '$,4(!,3!'$(0)!+%'.)%7!/,.+'()&%)'4F!$,5(E()@!'$#&'()%!(E,7.'0,+!<('$,-4!/%+!8(!.4(-! ',! 0<&),E(! %! <,-()%'(7;! %/'0E(! -(40?+()! (+:;<(! ',! ;0(7-! $0?$7;! %/'0E(! 80,/%'%7;4'4="VF!"Z_{!B(4&0'(!'$(4(!4.//(44(4@!0'!04!0<&,)'%+'!',!+,'(!'$%'!(%/$!4.//(443.7!} (9%<&7(!,3!'$(!%&&70/%'0,+!,3!#RB!<('$,-4!04!%//,<&%+0(-!8;!%!E%4'!+.<8()!,3!3%74(! &,40'0E(! )(4.7'4@! 4.??(4'0+?! %! 7%/6! ,3! .+-()4'%+-0+?! ,3! '$(! &$;40/%7! &)0+/0&7(4! '$%'! ?,E()+!(+:;<(!4')./'.)(!%+-!3.+/'0,+="[_{!*+!<,4'!/%4(4@!%!7%)?(!+.<8()!,3!(+:;<(!} -(40?+4! <.4'! 8(! '(4'(-! ',! 30+-! %! 3(5! %/'0E(! -(40?+4@! ;0(7-0+?! %! 7,5! 40?+%7! ',! +,04(! )%'0,=!A$(!%8070';!',!/,+404'(+'7;!-(40?+!%+!(+:;<(!3,)!%+;!-(40)(-!)(%/'0,+!)(<%0+4! '$(!L$,7;!?)%07N!,3!'$(!30(7-="ZI"W_!!

*+! '$04! /,+'(9'@! '$(! /,+')08.'0,+4! ,3! <;! 5,)6! /%+! 8(! /,+-(+4(-! -,5+! ',! '$)((!-033()(+'!4'.-0(4F!'$(4(!%)(!,.'70+(-!$()(!%+-!%)(!-(4/)08(-!0+!<,)(!-(&'$!0+! '$(!+(9'!/$%&'()4=!

(14)

! O!

*$#+','-%#+-)""$'$.#%/#"$0123('-#3-('&'(1##

R)0E(''!"(#3,4"G_{!)(&,)'(-!%+!0'()%'0E(!%&&),%/$!',!/,<&.'%'0,+%7!(+:;<(!-(40?+=!A$04!} %&&),%/$!0+/7.-(-!'$(!(E%7.%'0,+!,3!0+0'0%77;!0+%/'0E(!/,<&.'%'0,+%7!(+:;<(!-(40?+4! ',!-('()<0+(!'$(!/%.4(4!,3!0+%/'0E0';=!D<,+?!,'$()!'(/$+0T.(4@!<,7(/.7%)!-;+%<0/4! QHBS!40<.7%'0,+4!5()(!.4(-!',!-('()<0+(!4')./'.)%7!37%54!0+!'$(!-(40?+(-!(+:;<(4=! \0'$!'$04!0+3,)<%'0,+@!/$%+?(4!5()(!<%-(!0+!'$(!-(40?+!4')%'(?;!'$%'!;0(7-(-!%/'0E(! /%'%7;4'4! 3,)! '$(! ](<&! (70<0+%'0,+! Q]>S! )(%/'0,+=! A$04! )(4.7'! 4.??(4'(-! '$%'! HB! 40<.7%'0,+4!/,.7-!4()E(!%4!%!&)(I4/)((+0+?!4'(&!0+!'$(!#RB!3)%<(5,)6=!

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

!

5"+'.$'$.#-%$/%)23('%$3,#-63$."+#'$#"$012"+#

(15)

! U!

<%+;!<.4'!8(!%87(!',!%44.<(!'5,!,)!<,)(!-033()(+'!4')./'.)%7!,)!/$(<0/%7!4'%'(4!',! /%));! ,.'! '$(0)! 3.+/'0,+4=1F! 1YI1G_{! _,)! (9%<&7(@! 4,<(! (+:;<(4! <.4'! .+-()?,!} /,+3,)<%'0,+%7! /$%+?(4! ',! 8(! 3.+/'0,+%7=! A$(;! %74,! +((-! ',! 30+(7;! '.+(! '$(0)! %330+0'0(4! 3,)! 4.84')%'(4@! ')%+40'0,+! 4'%'(4@! %+-! &),-./'4! ',! /%'%7;:(! )(%/'0,+4! (330/0(+'7;F!0+!,'$()!5,)-4@!'$(;!<.4'!%/$0(E(!4(E()%7!-033()(+'!/$(<0/%7!4'%'(4=!!

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{! A$(! 37(908070';! '$%'! %77,54! 3,)!} '$(!/,+3,)<%'0,+%7!/$%+?(!0+!7,,&!V!04!&),E0-(-!8;!'5,!GI%<0+,!%/0-!$0+?(4!%'!'$(! 8(?0++0+?!%+-!%'!'$(!(+-!,3!'$(!7,,&=1W_{!A,!'(4'!'$(!&()3,)<%+/(!,3!HKB!%+-!(9&7,)(!} 0'4! %-E%+'%?(4! ,E()! KKB@! 5(! /,<&.'%'0,+%77;! -(40?+(-! A*H! 37(9087(! $0+?(4! .40+?! 8,'$! <('$,-4=! >9&()0<(+'%7! /$%)%/'()0:%'0,+! ,3! 4(7(/'(-! -(40?+4! )(E(%7(-! '$%'! /%7/.7%'0,+4! 3%E,)0+?! '$(! /7,4(-! 4'%'(! ,E()! '$(! ,&(+! 4'%'(! 5()(! <,)(! ),8.4'! %'! &)(-0/'0+?! $0?$7;! %+-! <,-()%'(7;! %/'0E(! <.'%+'4=! P.)! )(4.7'4! %74,! 0+-0/%'(-! '$%'! HKB! /,.7-! &()3,)<! 8(''()! '$%+! KKB! %'! )(/%&0'.7%'0+?! +%'.)%77;! ,84()E(-! $0+?(! 4(T.(+/(4=!!

(16)

! V!

&)(E0,.47;! ,84()E(-! 3,)! ,'$()! )(%/'0,+4! Q#$%&'()! **S@! '$(! HB! &),',/,7! /%+! -04/%)-! 3%74(!&,40'0E(!-(40?+4!%+-!/,))(/'7;!&)(-0/'!'$(!<,4'!%/'0E(!,+(4=!

!

7%83)!+#(6"#!"#$%&%#!"+'.$#%/#"$0123('-#3-('&'(1#

A$(!<,4'!4,.?$'I%3'()!?,%7!,3!/,<&.'%'0,+%7!(+:;<(!-(40?+!04!'$(!%8070';!',!)(70%87;! (+?0+(()!<%-(I',I,)-()!(+:;<(4="[_{!*+!#$%&'()!*`!,3!'$04!'$(404@!*!-(4/)08(!<;!(33,)'4!}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a[YYY! &),'(0+! 4')./'.)(4@! U! +,E(7! 4/%33,7-4! &%44(-! '$(! 8%''();! ,3! /,<&.'%'0,+%7! '(4'4!%7,+?!50'$!Z!+%'.)%7!A*H4!'$%'!5(!0+/7.-(-!%4!&,40'0E(!/,+'),74=!>9&()0<(+'%7! /$%)%/'()0:%'0,+! ,3! '$(! ',&I)%+6(-! -(40?+4! %+-! -(?(+()%'(! /,-,+! QB#S! E%)0%+'! 708)%)0(4!8%4(-!,+!'$(!U!+,E(7!4/%33,7-4!)(4.7'(-!0+!+,!%/'0E(!E%)0%+'4=!!

(17)

! Z!

(18)

! [!

! ! ! ! ! ! ! ! (

9,-7*&( :;:<( !"# $%&%'(( 6*&;'1*&&","-( 50( &"#$%42,1( 412,=,2$( 466/,&>( ,"( 2.&( 15%67242,5"4/( 6*52&,"( >&',-"( 0*4%&?5*@<(A$(! 4/$(<(! 077.4')%'(4! '$(! -(40?+! &),/(44=! A$(! HB! &),',/,7! $(7&4! )(-./(! '$(! +.<8()! ,3! (9&()0<(+'%7! '%)?('4! 8;! -04/%)-0+?!3%74(I&,40'0E(!4(T.(+/(4=!

(19)

! W!

!

! ( (

(

9,-7*&( :;A<#B*,5'&6.5'6.42&( ,'5%&*4'&( 4'( 4( 64*4>,-%( 05*( 15"05*%42,5"4/( 1.4"-&'( ,"( &"#$%42,1( 1424/$','<( C)D( PE()%77! 4')./'.)(! ,3! A*H! -(&0/'0+?! '$(! /,+3,)<%'0,+%7! /$%+?(! 8('5((+! '$(! ,&(+! Q,)%+?(! 7,,&S! %+-! /7,4(-! Q&.)&7(! 7,,&S! 4'%'(4<(CED(A*H!7,,&!V!(<&$%40:0+?!'$(!GI)(40-.(!CI'()<0+%7!QR`\S!%+-!#I'()<0+%7! Q]`DS!$0+?(4!%'!'$(!8(?0++0+?!%+-!(+-!,3!'$(!7,,&@!)(4&(/'0E(7;=!A$(!$0+?(4!&),E0-(! '$(!37(908070';!3,)!'$(!/,+3,)<%'0,+%7!/$%+?(=!C3D(A$(!A*H!)(%/'0,+!4/$(<(=!2,,&!Vb4! /7,4(-! /,+3,)<%'0,+! 04! )(4&,+4087(! 3,)! 4(T.(4'()0+?! '$(! )(%/'0,+! 0+'()<(-0%'(@! 5$0/$! 5,.7-! ,'$()504(! )(%/'! 50'$! 5%'()! %+-! (70<0+%'(! &$,4&$%'(! &),-./0+?! <('$;?7;,9%7@!%!$0?$7;!/;',',90/!<,7(/.7(=!!

! !

)(

E(

(20)

! "Y!

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

9,-7*&(:;F<(G1.&%&('.5?,"-(2.&(.,-.;2.*57-.672(15%67242,5"4/(?5*@0/5?(05*( >&',-","-(&"#$%&'(,"25(,"&*2('14005/>'<((

(21)

! ""!

H&0&*&"1&'(

"=! _()4$'@! D=! Q"WWWS=!:();-(;)"# 3$!# 2"-63$'+2# '$# <)%("'$# +-'"$-"=# ># .;'!"# (%# "$012"#-3(3,1+'+#3$!#<)%("'$#/%,!'$.@!\=!J=!_)((<%+=!

1=! J()4/$7%?@!B=!Q"W[[S=!A$(!),7(!,3!0+-./(-!30'!%+-!/,+3,)<%'0,+%7I/$%+?(4!,3! (+:;<(4!0+!4&(/030/0';!%+-!/%'%7;404=!?'%%).3$'-#@6"2'+()1!:I@!V1IWV=!

G=! \%)4$(7@!D=!Q"WW[S=!>7(/'),4'%'0/!,)0?0+!,3!'$(!/%'%7;'0/!&,5()!,3!(+:;<(4!%+-! '$(!),7(!,3!&)(,)?%+0:(-!%/'0E(!40'(4=!A#?'%,#@6"2!AJF@!1ZYGU=!

O=! ]+,57(4@!c=!X=!Q"WW"S=!>+:;<(!/%'%7;404^!C,'!-033()(+'@!M.4'!8(''()=!B3(;)"!FKL@! "1"I"1O=!

U=! B%$0;%'@!d=!*=!e!H%;,@!K=!2=!Q"WWVS=!R),'(0+!-(40?+!%.',<%'0,+=!C)%("'$#:-'"$-"! K@![WUIWYG=!

V=! D7E0:,! P@! D77(+! dB! e! H%;,! K2=! Q1YYZS=! #,<&.'%'0,+%7! &),'(0+! -(40?+! &),<04(4!',!)(E,7.'0,+0:(!&),'(0+!(+?0+(()0+?=!?'%("-6$'D;"+!MA@!G"fGU=!

Z=! B%$0;%'@!d=!*=!e!H%;,@!K=!2=!Q"WWZS=!B(!+,E,!&),'(0+!-(40?+^!_.77;!%.',<%'(-! 4(T.(+/(!4(7(/'0,+=!:-'"$-"!AJN@![1I[Z=!

[=! ].$7<%+@! d=@! B%+'%4@! g=@! *)(',+@! g=! #=@! `%)%+0@! g=@! K',--%)-@! d=! 2=! e! d%6()@! B=! Q1YYGS=! B(40?+! ,3! %! +,E(7! ?7,8.7%)! &),'(0+! 3,7-! 50'$! %',<0/I7(E(7! %//.)%/;=! :-'"$-"!FLA@!"GVOI"GV[=!

W=! H%7%6%.46%4@!K=!H=!e!H%;,@!K=!2=!Q"WW[S=!B(40?+@!4')./'.)(!%+-!4'%8070';!,3!%! $;&()'$()<,&$070/!&),'(0+!E%)0%+'=!B3(;)"#:();-(;)3,#?'%,%.1!K@!OZYIOZU=!

"Y=! d,7,+@! B=! C=! e! H%;,@! K=! 2=! Q1YY"S=! >+:;<(I706(! &),'(0+4! 8;! /,<&.'%'0,+%7! -(40?+=!C)%-""!'$.+#%/#(6"#B3('%$3,#>-3!"21#%/#:-'"$-"+#%/#(6"#E$'("!#:(3("+#%/# >2")'-3!ON@!"O1ZOI"O1ZW=!

""=! X,'$7048()?()@! B=@! ]$()4,+46;@! P=@! \,77%/,''@! D=! H=@! c0%+?@! 2=@! B(#$%+/0(@! c=@! d('6()@!c=@!g%77%$()@!c=!2=@!D7'$,33@!>=!D=@!h%+?$(770+0@!D=@!B;<@!P=@!D78(/6@!K=@!J,.6@! ]=! C=@! A%5306@! B=! K=! e! d%6()@! B=! Q1YY[S=! ](<&! (70<0+%'0,+! /%'%7;4'4! 8;! /,<&.'%'0,+%7!(+:;<(!-(40?+=!B3(;)"!MKF@!"WYIiO=!

(22)

! "1!

e! d%6()@! B=! Q1Y"YS=! #,<&.'%'0,+%7! -(40?+! ,3! %+! (+:;<(! /%'%7;4'! 3,)! %! 4'()(,4(7(/'0E(!80<,7(/.7%)!-0(74I%7-()!)(%/'0,+=!:-'"$-"!FAO@!GYWIG"G=!

"G=! R)0E(''@! J=! ]=@! ]044@! g=@! 2((@! A=! H=@! d7,<8()?@! X=@! #$0/%@! X=! D=@! A$,<%4@! 2=! H=@! J07E()'@! B=@! J,.6@! ]=! C=! e! H%;,@! K=! 2=! Q1Y"1S=! *'()%'0E(! %&&),%/$! ',! /,<&.'%'0,+%7! (+:;<(! -(40?+=! C)%-""!'$.+# %/# (6"# B3('%$3,# >-3!"21# %/# :-'"$-"+#%/#(6"#E$'("!#:(3("+#%/#>2")'-3!:LO@!GZWYIGZWU=!

"O=! ]$%)(@! K=! B=@! ]0&+04@! j=@! g)(04(+@! R=! c=@! A%6(./$0@! X=@! D4$%+0@! j=@! g,7-4<0'$@! H=@! K,+?@!j=!_=@!g%77%$()@!c=!2=@!K07<%+@!*=@!2(%-()@!J=@!K.44<%+@!c=!2=@!K',--%)-@!d=!2=@! A%5306@! B=! K=! e! d%6()@! B=! Q1Y"1S=! #,<&.'%'0,+%7! )(-(40?+! ,3! %! <,+,+./7(%)! :0+/! <('%77,(+:;<(! 3,)! ,)?%+,&$,4&$%'(! $;-),7;404=! B3(;)"# @6"2'-3,# ?'%,%.1!N@!1WOIGYY=!

"U=! J07E()'@! B=! Q1YYYS=! #)0'0/%7! %+%7;404! ,3! %+'08,-;! /%'%7;404=!>$$;3,# F"&'"8# %/# ?'%-6"2'+()1!IO@!ZU"IZWG=!

"V=! d7,<8()?@!X=@!])0(4@!J=@!R0+6%4@!B=!H=@!H0''7@!R=!X=!>=@!g).''()@!H=!g=@!R)0E(''@!J=!]=@! H%;,@!K=!2=!e!J07E()'@!B=!Q1Y"GS=!R)(/040,+!04!(44(+'0%7!3,)!(330/0(+'!/%'%7;404!0+! %+!(E,7E(-!6(<&!(70<0+%4(=!B3(;)"!KLF@!O"[Ik=!

"Z=! ])0(4@! J=@! d7,<8()?@! X=! e! J07E()'@! B=! Q1Y"GS=! B(! +,E,! (+:;<(4! 8;! /,<&.'%'0,+%7!-(40?+=!@;))"$(#G<'$'%$#'$#@6"2'-3,#?'%,%.1!:J@!11"I11[=!

"[=! d%6()@!B=!Q1Y"YS=!D+!(9/0'0+?!8.'!/$%77(+?0+?!),%-!%$(%-!3,)!/,<&.'%'0,+%7! (+:;<(!-(40?+=!C)%("'$#:-'"$-"!:O@!"["ZI"["W=!

"W=! d,7,+@!B=!C=@!`,0?'@!#=!D=!e!H%;,@!K=!2=!Q1YY1S=!B(!+,E,!-(40?+!,3!80,/%'%7;4'4=! @;))"$(#G<'$'%$#'$#@6"2'-3,#?'%,%.1!I@!"1UI"1W=!

1Y=! g()4'(0+@! H=@! 2(46@! D=! H=! e! #$,'$0%@! #=! Q"WWOS=! K')./'.)%7! <(/$%+04<4! 3,)! -,<%0+!<,E(<(+'4!0+!&),'(0+4=!?'%-6"2'+()1!FF@!VZGWIVZOW=!

1"=! J%<<(4@!g=!g=!Q1YY1S=!H.7'0&7(!/,+3,)<%'0,+%7!/$%+?(4!0+!(+:;<(!/%'%7;404=! ?'%-6"2'+()1!M:@![11"I[11[=!

11=! J(+:7()I\07-<%+@! ]=! e! ]()+@! B=! Q1YYZS=! B;+%<0/! &()4,+%70'0(4! ,3! &),'(0+4=! B3(;)"!MKL@!WVOIWZ1=!

(23)

! "G!

Q1YYZS=!*+')0+40/!<,'0,+4!%7,+?!%+!(+:;<%'0/!)(%/'0,+!')%M(/',);=!B3(;)"!MKL@! [G[Ii"G=!

1O=! D77(+@!d=!B=!e!H%;,@!K=!2=!Q1Y"YS=!D+!(330/0(+'!%7?,)0'$<!3,)!<.7'04'%'(!&),'(0+! -(40?+!8%4(-!,+!3%4'()=!A%;)$3,#%/#@%2<;(3('%$3,#@6"2'+()1!F:@!WYOIW"V=!

1U=! \0770%<4@! c=! #=! e! H/-()<,''@! D=! >=! Q"WWUS=! B;+%<0/4! ,3! '$(! 37(9087(! 7,,&! ,3! ')0,4(&$,4&$%'(! 04,<()%4(! I! '$(! 7,,&! <,'0,+! 04! +,'! 70?%+-I?%'(-=! ?'%-6"2'+()1!FM@![GYWI[G"W=!

1V=! K.+@!c=!e!K%<&4,+@!C=!K=!Q"WWWS=!i+-()4'%+-0+?!&),'(0+!70-4^!]0+('0/!%+%7;404! ,3! %/'0E(! $0+?(! <.'%+'4! 0+! ')0,4(&$,4&$%'(! 04,<()%4(=! ?'%-6"2'+()1! FN@! ""OZOI""O["=!

1Z=! K.+@! K=! J=! e! K%<&4,+@! C=! K=! Q"WW[S=! B('()<0+%'0,+! ,3! '$(! %<0+,! %/0-! )(T.0)(<(+'4! 3,)! %! &),'(0+! $0+?(! 0+! ')0,4(&$,4&$%'(! 04,<()%4(=! C)%("'$# :-'"$-"!J@!"OWUI"UYU=!

1[=! l0%+?@! c=! j=@! K.+@! c=! J=! e! K%<&4,+@! C=! K=! Q1YY"S=! A$(! 0<&,)'%+/(! ,3! $0+?(! 4(T.(+/(!3,)!7,,&!3.+/'0,+!%+-!/%'%7;'0/!%/'0E0';!0+!'$(!)(%/'0,+!/%'%7;:(-!8;! ')0,4(&$,4&$%'(!04,<()%4(=!A%;)$3,#%/#H%,"-;,3)#?'%,%.1!FLJ@!""YGI"""1=!

1W=! \0()(+?%@!X=!]=@!]%&('%+0,.@!>=!g=!e!`(+6%'(4%+@!X=!Q1Y"YS=!A)0,4(&$,4&$%'(! 04,<()%4(^!D!$0?$7;!(E,7E(-!80,/%'%7;4'=!@",,;,3)#3$!#H%,"-;,3)#I'/"#:-'"$-"+! IJ@!GWV"IGW[1=!

GY=! #.0@!m=!e!]%)&7.4@!H=!Q1YYGS=!#%'%7;404!%+-!4&(/030/0';!0+!(+:;<(4^!D!4'.-;!,3! ')0,4(&$,4&$%'(! 04,<()%4(! %+-! /,<&%)04,+! 50'$! <('$;7! ?7;,9%7! 4;+'$%4(=! C)%("'$#:'2;,3('%$+!II@!G"UIk=!

G"=! ]+,57(4@! c=! X=! e! D78();@! \=! c=! Q"WZZS=! R()3(/'0,+! 0+! (+:;<(! /%'%7;404! I! (+()?('0/4!,3!')0,4(&$,4&$%'(!04,<()%4(=!>--%;$(+#%/#@6"2'-3,#F"+"3)-6!:L@! "YUI"""=!

!

(24)

! "#!

!

$%&'()*!++!

!

!"#$%&%'(!,-*))./.0!12!3.456&(/-!7-(/8/(59!7!

:1;)-<;&*!=5.&6/->!7''*1&-%!

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

(25)

! "?!

"#$%&'(%!!

(26)

! "R!

)*%&+,-(%.+*!

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

(27)

! "P!

%/0%L(%*1<0%'<(!>-*))./.0!6)(%1@>E!U%)!-16'<(&(/1.&;!'*1()/.!@)>/0.!2*&6)I1*J! I1<;@! (%<>! D).)2/(! 2*16! %&8/.0! &.!%"# 3%&%'(#'*)L>-*))./.0! >()'! (%&(! />! -&'&D;)! 12! *);/&D;5!*&.J/.0!>(*<-(<*)>!&--1*@/.0!(1!(%)/*!-&(&;5(/-!'*1')*(/)>E!!

$16'<(&(/1.&;! (11;>! %&8)! '*)8/1<>;5! D)).! <>)@! (1! F<&.(/25! ).456&(/-! -&(&;5>/>E"YL"#_{! +.! '&*(/-<;&*G! M&*>%);!} _{.-# +&8}"VK! "?_{! &.@! T&66)>L,-%/22)*!} _{.-# +&8}"R_! /.@)').@).(;5! &'';/)@! (%)! )6'/*/-&;! 8&;).-)! D1.@! A3ZSC! 6)(%1@! (1! &! >6&;;! >)(! 12! ).456)>E! 7;(%1<0%! )H-);;).(! -1**);&(/1.! D)(I)).! -&;-<;&()@! &.@! )H')*/6).(&;! -&(&;5(/-! *&()>! I&>! *)'1*()@G! .)/(%)*! 12! (%)>)! >(<@/)>! &.&;54)@! /.&-(/8)! 6<(&.(>E! U%)*)21*)! (%)5! @/@! .1(! &>>)>>! (%)! 6)(%1@[>! &D/;/(5! (1! @/>(/.0</>%! &-(/8)! 6<(&.(>! 2*16! /.&-(/8)! 1.)>G! I%/-%! />! -*/(/-&;! /.! *.# "(<(! ).456)! @)>/0.! &'';/-&(/1.>E! 7@@/(/1.&;;5! T1<J! .-# +&8"P_# _{<(/;/4)@! :=! (1! F<&;/(&(/8);5! &.&;54)! -16'<(&(/1.&;;5!} @)>/0.)@! ).456)>E! 7;(%1<0%! *)&>1.&D;)! &0*))6).(! D)(I)).! )H')*/6).(&;! *)><;(>! &.@! :=! '*)@/-(/1.>! I&>! 21<.@G! 1.;5! 1.)! *)&-(/1.! I&>! >(<@/)@! &.@! (%<>! (%)! 0).)*&;/(5!12!(%)!6)(%1@!I&>!.1(!()>()@E!!

(28)

! "^!

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

+.! (%)! 21;;1I/.0! >)-(/1.>G! I)! @)>-*/D)! %1I! (%)! :=! '*1(1-1;! I&>! 1'(/6/4)@! &.@! ()>()@! 21*! *)'*1@<-/D/;/(5G! &--<*&-5G! &.@! (*&.>2)*&D/;/(5! (1! 1(%)*! *)&-(/1.>E! U1! &;;1I!21*!;&*0)L>-&;)!>-*))./.0G!(%)!'*1(1-1;!/>!@)>/0.)@!(1!'*)>)*8)!-16'<(&(/1.&;! )22/-/).-5E!M)!<>)@!/.!(1(&;!18)*!"PO!@/22)*).(!>(*<-(<*)>!&/6)@!&(!-&(&;54/.0!)/(%)*! 12!(I1!*)&-(/1.>9!(%)!])6'!);/6/.&(/1.!12!?L./(*1D).4/>1H&41;)!A`SaC!1*!(%)!$;&/>).! *)&**&.0)6).(!12!-%1*/>6&()E!N<*!*)><;(>!><00)>(!(%&(!(%)!:=!'*1(1-1;!/>!0).)*&;G! &.@! )H-);>! &(! @/>-&*@/.0! 2&;>)L'1>/(/8)! @)>/0.>! I%/;)! '*)@/-(/.0! (%)! 61>(! &-(/8)! ).456)>!-1**)-(;5E!!

!

/0$-1%$!'*,!2.$(-$$.+*!

=,-%1%>+-%("#(/#-4.#,0(-('(&#

(29)

! "Q!

()>()@!AX/0<*)!YLYCE!M)!<>)@!(%)!^!])6'!);/6/.&(/1.!@)>/0.>!*)'1*()@!D5!B*/8)((!.-# +&8"O_{!&>!&!(*&/./.0!>)(!AU&D;)!YL"CE!_/8).!(%&(!(%)!J)5!-1.(&-(!/.!(%)!&-(/8)!>/()!/>!(%)!} %5@*10).! D1.@! D)(I)).! (%)! 0).)*&;! D&>)! A7>'! 1*! _;<C! &.@! (%)! %5@*10).! 1.! (%)! ><D>(*&()G! (%/>! @/>(&.-)! I&>! 61./(1*)@! @<*/.0! (%)! >/6<;&(/1.! &.@! I&>! <>)@! (1! '*)@/-(! &-(/8/(5! AX/0<*)! YL"SCE! ,(*<-(<*)>! (%&(! 6&/.(&/.)@! (%/>! -1.(&-(! @<*/.0! (%)! >/6<;&(/1.! A(/6)L&8)*&0)! @/>(&.-)! b! VEYO! cGYOK! Y"_{C! I)*)! '*)@/-()@! (1! D)! &-(/8)G!} I%)*)&>!(%1>)!(%&(!@/@!.1(!I)*)!'*)@/-()@!(1!D)!/.&-(/8)E!!

+.!(%)!2/*>(!8)*>/1.!12!1<*!>-*))./.0!&''*1&-%!AX/0<*)!YLYCG!6/./6/4&(/1.!I&>! ')*21*6)@!(1!);/6/.&()!-;&>%)>!I/(%!I&()*!61;)-<;)>!I%/;)!J))'/.0!&;;!.1.LI&()*G! .1.L%5@*10).!&(16>!2/H)@E!U%/>!I&>!21;;1I)@!D5!&!%)&(/.0!'%&>)!(1!D*/.0!(%)!>5>()6! (1!(%)!(&*0)(!()6')*&(<*)!AVOO!]CE!7.!)F</;/D*&(/1.!>()'!I&>!@1.)!&(!`BU!-1.@/(/1.>! AVOO! ]! &.@! "! &(6CE! S5! 61./(1*/.0! ()6')*&(<*)G! '*)>><*)G! *&@/<>! 12! 05*&(/1.G! &.@! \:,=G!I)!).><*)@!(%&(!(%)!>5>()6!I&>!)F</;/D*&()@E!X/.&;;5G!(%)!'*1@<-(/1.!'%&>)! -1.>/>()@!12!YO!.>!12!`BU!:=E!!

(30)

! YO!

@/>(&.-)>!Af!VEY!cCE!U%)!:=!*)><;(>!/.@/-&()!(%&(!(%)!><D>(*&()!*)6&/.>!D1<.@!(1!(%)!

&-(/8)!>/()!@<*/.0!(%)!).(/*)!>/6<;&(/1.E!U%<>G!T_LY!/>!'*)@/-()@!(1!D)!&-(/8)E!=)>'/()!

(%)>)!><--)>>2<;!'*)@/-(/1.>G!(%)!'*1(1-1;!I&>!.1(!&--<*&()!).1<0%!(1!D)!<>)2<;E!N.;5!

(%*))! 12! (%)! )/0%(! @)>/0.>! I)*)! '*)@/-()@! -1**)-(;5! AU&D;)! YL"CE! 7! 61*)! @)(&/;)@!

&.&;5>/>! 12! (%)! >/6<;&(/1.>! *)8)&;)@! (%&(! (%)! 2/*>(! (%*))! >()'>! 12! B*1(1-1;! "!

A6/./6/4&(/1.G!%)&(/.0G!&.@!)F</;/D*&(/1.C!I)*)!-16';)();5!@/>*<'(/.0!(%)!>(*<-(<*)!

12! >16)! 12! (%)! @)>/0.>E! X1*! /.>(&.-)G! (%)! D/.@/.0! &.@! -&(&;5(/-! -1.(&-(>! 12! 1(%)*!

@)>/0.>! /.! (%)! (*&/./.0! >)(G! I)*)! ;1>(! &2()*! )F</;/D*&(/1.! 12! (%)! >5>()6E! +.! ;/0%(! 12!

(%)>)!1D>)*8&(/1.>G!I)!@)-/@)@!(1!61@/25!(%)!'*1(1-1;!(1!/.-;<@)!*)>(*&/.(>!1.!(%)!

&-(/8)!>/()!*)>/@<)>!/.!1*@)*!(1!J))'!(%)!>(*<-(<*)!&>!-;1>)!&>!'1>>/D;)!(1!(%)!@)>/0.!

>(*<-(<*)G!&(!;)&>(!<.(/;!(%)!).@!12!(%)!)F</;/D*&(/1.E!

M)!(%)*)21*)!@)8/>)@!B*1(1-1;!Y!AX/0<*)!YLYCE!U%)!6&/.!@/22)*).-)!D)(I)).!

(%/>!'*1-)@<*)!&.@!B*1(1-1;!"!/>!(%&(!%&*61./-!*)>(*&/.(>!&*)!&'';/)@!(1!(%)!&-(/8)!

>/()! *)>/@<)>! &.@! ><D>(*&()! @<*/.0! (%)! %)&(/.0! A21*-)! -1.>(&.(! )F<&;! (1! ?O!

J-&;g61;g7Y_{C!&.@!)F</;/D*&(/1.!>()'>!A!21*-)!-1.>(&.(!>(&*(/.0!2*16!?O!J-&;g61;g7}Y!

&.@!0*&@<&;;5!*);)&>/.0!(1!O!J-&;g61;g7Y_{CE!!B*1(1-1;!Y!5/);@)@!'*)@/-(/1.>!(%&(!&*)!}

61*)! -1.>/>().(! I/(%! )H')*/6).(&;! *)><;(>G! I/(%! 2/8)! 12! )/0%(! @)>/0.>! '*)@/-()@!

-1**)-(;5! AU&D;)! YL"CE! T1I)8)*G! "7?VL"! &.@! "UTXL"G! D1(%! /.&-(/8)! @)>/0.>! A2&;>)!

'1>/(/8)>CG! I)*)! &0&/.! '*)@/-()@! (1! D)! &-(/8)E! X<*(%)*! &.&;5>/>! '*18/@)@! >16)!

8&;<&D;)!;)>>1.>E!h>/.0!1.;5!(%)!2/*>(!"O!.>!12!>/6<;&(/1.!*)><;()@!/.!)H&-(;5!(%)!>&6)!

'*)@/-(/1.>! &>! <>/.0! YO! .>K! (%)*)21*)G! (%)! (/6)! 12! (%)! '*1@<-(/1.! '%&>)! -1<;@! D)!

(31)

! Y"!

(%&(!W<>(!&.!)F</;/D*&(/1.!&(!(%)!(&*0)(!()6')*&(<*)!6/0%(!D)!).1<0%!(1!)F</;/D*&()!

(%)!>5>()6E!!

U1!)H';1*)!(%)!/6'&-(!12!(%)>)!-%&.0)>!1.!1<*!>-*))./.0!(11;G!I)!21*6<;&()@!

(I1!61*)!'*1(1-1;>!AB*1(1-1;>!V!&.@!#G!X/0<*)!YLYCE!U%)!6/./6/4&(/1.!>()'!I&>!(%)!

>&6)! &>! D)21*)E! T1I)8)*G! (%)! %)&(/.0! '%&>)! I&>! .1(! /.-;<@)@G! &.@! %&*61./-!

*)>(*&/.(>!I)*)!&'';/)@!1.!&;;!.1.LI&()*G!.1.L%5@*10).!&(16>!@<*/.0!)F</;/D*&(/1.E!

U%)! 21*-)! -1.>(&.(>! 21*! (%)>)! *)>(*&/.(>! I)*)! 0*&@<&;;5! *);)&>)@! 2*16! ?O!

J-&;g61;g7Y_{!<>/.0!(%)!21;;1I/.0!;11'9!!]i?Og#}/_{G!/!i!OG!"G!Y!j!?E!!U%)!'*1@<-(/1.!'%&>)!}

I&>!&;>1!@/22)*).(E!B*1(1-1;!V!<>)@!<.*)>(*&/.)@!:=!1.!&;;!&(16>G!I%)*)&>!B*1(1-1;!

#!&'';/)@!*)>(*&/.(>!1.!.1.L&-(/8)!>/()!*)>/@<)>!<>/.0!&!;1I!21*-)!-1.>(&.(!A]i?Og#?!

J-&;g61;g7Y_{CE!+.!D1(%!-&>)>G!(%)!'*1@<-(/1.!'%&>)!I&>!1.;5!"O!.>E!!}

S1(%! '*1(1-1;>! '*1@<-)@! *)><;(>! (%&(! I)*)! /.! &0*))6).(! I/(%! (%)!

)H')*/6).(&;! @&(&! 21*! (%)! (*&/./.0! >)(! AU&D;)! YL"CE! UI1! 12! (%)! (%*))! 2&;>)! '1>/(/8)!

@)>/0.>! /.! (%)! (*&/./.0! >)(! I)*)! @/>-&*@)@G! I%/;)! &;;! 12! (%)! &-(/8)! @)>/0.>! I)*)!

-1**)-(;5! '*)@/-()@E! U%)>)! *)><;(>! ><00)>()@! (%&(! B*1(1-1;>! V! &.@! #! -1<;@! 5/);@!

<>)2<;!'*)@/-(/1.>!I/(%!1.;5!"O!.>!12!>/6<;&(/1.!(/6)E!!

!

$%12&+-%("#+"*#+"+&;3%3#(/#-4.#?@#.">;1.#*.3%A".*#B;#\k(%;/>D)*0)*!.-#+&8C_!

M)! .1I! &'';5! (%)! >-*))./.0! &''*1&-%! (1! &! ;&*0)*! &.@! 61*)! @/8)*>)! >)(! 12! ]3!

).456)>! (%&(! %&@! D)).! -16'<(&(/1.&;;5! @)>/0.)@! D5! \k(%;/>D)*0)*!.-# +&!#_{E! +.! (%&(!}

>(<@5G!-16'<(&(/1.&;!6)(%1@>!I)*)!<>)@!(1!@)>/0.!-&.@/@&()!>)F<).-)>E!X/2(5L./.)!

@)>/0.>! A/.! >)8).()).! @/22)*).(! >-&221;@>C! I)*)! >);)-()@! 21*! )H')*/6).(&;!

(32)

! YY!

B*1(1-1;>! V! &.@! #! I)*)! *<.! /.! (*/';/-&()G! <>/.0! @/22)*).(! *&.@16! .<6D)*!

>))@>G!21*!?O!12!(%)!]3!@)>/0.>!*)'1*()@!D5!\k(%;/>D)*0)*!.-#+&8D#_{!I%/-%!/.-;<@)@!(%)!} ^!&-(/8)!).456)>E!7>!>)).!/.!U&D;)!YLY!&.@!X/0<*)!YLVG!B*1(1-1;!V!-1**)-(;5!'*)@/-()@!

R!12!(%)!^!&-(/8)!@)>/0.>!A>).>/(/8/(5!12!OEP?CG!I%)*)&>!B*1(1-1;!#!1.;5!@/@!>1!21*!#!

@)>/0.>! A>).>/(/8/(5! 12! OE?OCE! +.! D1(%! -&>)>G! (%)! (I1! 61>(! &-(/8)! ).456)>! I)*)!

&61.0!(%1>)!'*)@/-()@!-1**)-(;5E!N.!(%)!1(%)*!%&.@G!D1(%!'*1(1-1;>!)H%/D/()@!%/0%!

>')-/2/-/(5!AOEP"CG!I%/-%!6)&.>!(%&(!P"l!12!2&;>)!'1>/(/8)>!&*)!D)/.0!@/>-&*@)@E!+.!

&@@/(/1.G! D1(%! '*1(1-1;>! >%1I)@! %/0%! AOEQ#C! .)0&(/8)! '*)@/-(/8)! 8&;<)! A`BZCG!

6)&./.0! (%&(! Q#l! 12! (%)! @)>/0.>! (%&(! &*)! '*)@/-()@! &>! /.&-(/8)! &*)! /.@))@!

)H')*/6).(&;;5!/.&-(/8)E!7@@/(/1.&;;5G!B*1(1-1;!V!)H%/D/(>!%/0%)*!'1>/(/8)!'*)@/-(/8)!

8&;<)! ABBZC! (%&.! B*1(1-1;! #E! `1()! &;>1! (%&(! (%)! >6&;;! )**1*! D&*>! /.! X/0<*)! YLV!

/.@/-&()! (%&(! 1<*! '*1(1-1;>! &*)! *)'*1@<-/D;)E! ,/.-)! (%)>)! *)><;(>! >%1I)@! (%&(!

B*1(1-1;! V! I&>! (%)! D)>(! '*1(1-1;! ()>()@G! I)! @)-/@)@! (1! <>)! /(! 21*! (%)! *)>(! 12! 1<*!

>/6<;&(/1.>E!E!+2!I)!I)*)!(1!<>)!B*1(1-1;!VG!/.>()&@!12!%&8/.0!(1!@1!)H')*/6).(>!1.!

2/2(5! -&.@/@&()! @)>/0.>! (1! 2/.@! )/0%(! &-(/8)! 1.)>G! I)! I1<;@! 1.;5! %&8)! (1! *<.!

)H')*/6).(>! 1.! )/0%()).! -&.@/@&()! >)F<).-)>! (1! 2/.@! >/H! &-(/8)! @)>/0.>G! I%/-%!

/.-;<@)!(%)!(I1!61>(!&-(/8)!1.)>!AU&D;)!YLYCE!

N<*! >/6<;&(/1.>! *)8)&;)@! (%&(! 21*! 61>(! 12! (%)! @)>/0.>! '*)@/-()@! (1! D)!

/.&-(/8)G!-16'<(&(/1.&;;5!@)>/0.)@!&-(/8)!>/()!0)16)(*/)>!&*)!@/>*<'()@!)&*;5!/.!(%)!

>/6<;&(/1.!AI/(%/.!(%)!2/*>(!V!.>CG!)8/@).-/.0!&!;&-J!12!>(*<-(<*&;!/.()0*/(5!I/(%/.!(%)!

D/.@/.0!'1-J)(E!X1*!)H&6';)G!1.)!-1661.!2&/;<*)!/>!(%&(!(%)!0).)*&;!D&>)!1*!(%)!mL

>(&-J/.0!*)>/@<)!A-&(&;5(/-!*)>/@<)>!/.!(%)!]3!&-(/8)!>/()G!X/0<*)!YL"SC!2;/'>!1<(!12!(%)!

(33)

! YV!

><D>(*&()E!7>!&!*)><;(G!(%)!><D>(*&()!618)>!(1!&!2/.&;!.1.L-&(&;5(/-!'1>/(/1.!I/(%/.!(%)!

&-(/8)! >/()! 1*! -16';)();5! @/22<>)>! &I&5! 2*16! (%)! '1-J)(G! *).@)*/.0! &! '*)@/-()@!

/.&-(/8)!@)>/0.E!

!

60+"3/.0+B%&%-;# -(# +"(-4.0# .">;1+-%'# 0.+'-%("E# 64.# F&+%3."# 0.+00+"A.1."-# (/#

'4(0%31+-.#

+.!&!(%/*@!>)(!12!()>(>G!I)!&'';5!B*1(1-1;!V!(1!(%)!>(<@5!12!-%1*/>6&()!6<(&>)>!A$:>CE!

$:!-&(&;54)>!(%)!D/1;10/-&;;5!*);)8&.(!<./61;)-<;&*!*)&**&.0)6).(!12!-%1*/>6&()!(1!

'*)'%).&()G! &! $;&/>).! *)&**&.0)6).(! AX/0<*)! YL#7CE! U%)! *)&-(/1.! />! '&*(! 12! (%)!

D/1>5.(%)(/-! '&(%I&5! 12! &*16&(/-! &6/.1! &-/@>! ><-%! &>! (*5'(1'%&.! &.@! (5*1>/.)E! +(!

%&>!&!8)*5!I);;!-%&*&-()*/4)@!-%)6/>(*5YYLY?_{!&.@!%&>!D)).!(%)!><DW)-(!12!*)>)&*-%!/.!}

1<*! ;&D! 21*! >)8)*&;! 5)&*>EYR_{! M)! D&>)@! 1<*! >(<@5! 1.! $:! 6<(&.(>! (%&(! %&@! D)).!}

'*)8/1<>;5! >(<@/)@! D5! n&>>/;&!.-# +&8YP_{! +.! (%&(! I1*JG! )H%&<>(/8)! 6<(&0).)>/>! I&>!}

-&**/)@!1<(!1.!>/H!>)-1.@&*5!&-(/8)!>/()!*)>/@<)>G!5/);@/.0!21*(5!&-(/8)!6<(&.(>!&.@!

>)8).(5L21<*!/.&-(/8)!1.)>!AX/0<*)!YL#SCE!

U%)!0)16)(*/-!-*/()*/&!&''*1'*/&()!21*!&.&;5>/>!12!:=!(*&W)-(1*/)>!@)').@!1.!

(%)! *)&-(/1.E! X1*! (%)! *)&**&.0)6).(! 12! -%1*/>6&()G! I)! 61./(1*)@! (%)! @/>(&.-)!

D)(I)).! (%)! (I1! -&*D1.>! (%&(! I/;;! 21*6! &! D1.@! /.! (%)! '*1@<-(! A%8.EG! (%)! $RL$^!

@/>(&.-)C! &.@! <>)@! &! -<(L122! @/>(&.-)! 12! VE?! c! &>! -*/()*/&Y^_{AX/0<*)! YL?CE! B*)8/1<>!}

>(<@/)>! %&8)! >%1I.! (%&(! (%)! ).456)! -&(&;54)>! (%/>! *)&-(/1.! D)-&<>)! (%)! @/L&H/&;!

-1.2/0<*&(/1.!A*)&-(/8)!-1.2/0<*&(/1.C!12!(%)!><D>(*&()!/>!61*)!2&81*)@!/.!(%)!&-(/8)!

>/()!(%&.!/.!I&()*K!/.!I&()*G!(%)!@/L)F<&(1*/&;!-1.2/0<*&(/1.!/>!61*)!>(&D;)EY^_{!_/8).!}

(34)

! Y#!

).456)! (1! D)! &-(/8)G! &.@! (%)*)21*)! @)-/@)@! (1! &;>1! 61./(1*! (%)! *);)8&.(! @/%)@*&;!

&.0;)!A%8.8D!N#L$VL$#LN"C!AX/0<*)!YL?CE!

M/;@L(5')!@3'4.0%'4%+# '(&%! $:! AB=S! +=9! "3$:C! &.@! /(>! ""#! >/.0;)! 6<(&.(>G!

I/(%! -%1*/>6&()! D1<.@! (1! (%)! &-(/8)! >/()! /.! (%)! @/L&H/&;! -1.21*6&(/1.G! I)*)!

><DW)-()@!(1!:=!>/6<;&(/1.>E!U5'/-&;!:=!*)><;(>!1D(&/.)@!21*!(%/>!>)(!12!).456)>!&*)!

/;;<>(*&()@!D5!I/;@L(5')!$:!A"3$:C!&.@!/(>!)H')*/6).(&;;5!/.&-(/8)!6<(&.(!"3$:L

=#^+!AX/0<*)!YLRCE!!X1*!(%)!I/;@L(5')!).456)G!(%)!><D>(*&()!$^L$R!@/>(&.-)!I&>!8)*5!

;1-&;/4)@! &(! VEVY! cE! 7.&;5>/>! 12! (%)! @/%)@*&;!&.0;)>! >%1I)@! (%&(! (%)! ><D>(*&()! &;>1!

*)(&/.)@!&!@/L&H/&;!-1.2/0<*&(/1.!AN#L$VL$#LN"!@/%)@*&;!&.0;)!o!!"VQ°CE!+.!-1.(*&>(G!

"3$:L=#^+!%&@!&.!&8)*&0)@!$^L$R!@/>(&.-)!12!VEQ!cK!/.!&@@/(/1.G!&!(*&.>/(/1.!&(!YE?!

.>!-1**)>'1.@/.0!(1!&!2/.&;!@/L)F<&(1*/&;!-1.21*6&(/1.!I&>!1D>)*8)@E!=/%)@*&;!&.0;)!

8>E!(/6)!';1(>!&;>1!)H%/D/(!&!(*&.>/(/1.!&(!YE?!.>!(1!&!-1.21*6&(/1.&;!>(&()!-1.>/>().(!

I/(%! &! 2/.&;! @/L)F<&(1*/&;! -1.2/0<*&(/1.! 12! (%)! ><D>(*&()! AN#L$VL$#LN"! @/%)@*&;!

&.0;)!o!!QO°CE!

U%)! *)><;(>! &.@! -1.-;<>/1.>! 21*! (%)! $:! 6<(&.(>! I)*)! -16'&*&D;)! (1! (%1>)!

1D(&/.)@! 21*! (%)! ]3! ).456)>! AX/0<*)! YLP! &.@! U&D;)! YL#CE! 7>! /.! (%)! -&>)! 12! (%)! ]3!

).456)>G! (%)! 61>(! &-(/8)! 6<(&.(>! &*)! '*)@/-()@! -1**)-(;5G! &.@! (%)! 6&W1*/(5! 12! (%)!

6<(&.(>! @/>-&*@)@! D5! (%)! '*1(1-1;! &*)! /.@))@! /.&-(/8)! A%/0%! `BZCE! +(! />! I1*(%!

.1(/-/.0!(%&(!(%/>!()>(!I&>!-%&;;).0/.0!/.!6&.5!I&5>E!+(!/.81;8)@!&!@/22)*).(!*)&-(/1.G!

D<(!61*)!/6'1*(&.(;5G!(%)!>(*<-(<*&;!@/22)*).-)>!D)(I)).!(%)!6<(&.(>!&.@!(%)!I/;@L

(5')! ).456)! I)*)! 6/./6&;p1.;5! >/.0;)! 6<(&.(>! I)*)! &.&;54)@E! U%)>)! *);&(/8);5!

6/.1*! >(*<-(<*&;! @/22)*).-)>! '*18/@)! &! >(*/.0).(! ()>(! 12! (%)! '*1(1-1;d>! &D/;/(5! (1!

(35)

! Y?!

2/.@/.0>!><00)>(!(%&(!(%)!0)16)(*/-!-*/()*/&LD&>)@!:=!'*1(1-1;!-&.!D)!><--)>>2<;;5!

(*&.>2)**)@!(1!&!@/22)*).(!*)&-(/1.E!

!

F(1,2-+-%("+&#,.0/(01+"'.!

$16'<(&(/1.&;!')*21*6&.-)!12!:=!>/6<;&(/1.>!@)').@>!1.!6&.5!2&-(1*>G!/.-;<@/.0!

(%)!>/4)!12!(%)!>5>()6G!(%)!-<(122!@/>(&.-)G!B:3G!)(-EYQ_{!+(!I&>!(%)*)21*)!/6'1*(&.(!(1!}

@)()*6/.)!(%)!')*21*6&.-)!&.@!>-&;&D/;/(5!12!1<*!'*1(1-1;!1.!(%)!(5')!12!>5>()6!I)!

/.().@)@!(1!I1*J!1.E!X/0<*)!YL^!>%1I>!&.!&>>)>>6).(!12!B*1(1-1;!Vd>!')*21*6&.-)!

1.! $BhL1.;5! &.@! $BhL_Bh! -1.2/0<*&(/1.>E! h>/.0! _BhL$Bh! -;<>()*>! -&.! D)! &.!

/.()*)>(/.0! &;()*.&(/8)! D)-&<>)! /(! '*18/@)>! &! ?L! (1! "OL21;@! /6'*18)6).(! /.!

')*21*6&.-)E!!

!

3+*(1-$.+*$!

S5! 6&J/.0! *&(/1.&;LD&>)@! 61@/2/-&(/1.>! (1! 1<*! '*1(1-1;G! I)! @)8);1')@! &.! )H';/-/(!

>1;8).(! 61;)-<;&*! @5.&6/->! &''*1&-%! (1! '*)L>-*)).! ).456)! @)>/0.>E! U%)! *)><;(>!

><00)>(!(%&(!1<*!6)(%1@1;105!/>!0).)*&;G!*)'*1@<-/D;)G!&.@!-&.!@/>-&*@!2&;>)!'1>/(/8)!

@)>/0.>!I%/;)!'*)@/-(/.0!(%)!61>(!&-(/8)!@)>/0.>!-1**)-(;5E!+.!&@@/(/1.G!(%)!6)(%1@!

>))6>! (1! D)! *)&@/;5! (*&.>2)*&D;)! (1! 1(%)*! -%)6/>(*/)>E! U%)! 61>(! &''*1'*/&()!

0)16)(*/-! -*/()*/&! (1! D)! <>)@! I/(%! (%)! '*1(1-1;! I/;;! @)').@! 1.! (%)! *)&-(/1.! &.@!

'*1'1>)@! 6)-%&./>6G! &.@! >%1<;@! D)! @)()*6/.)@! D&>)@! 1.! -%)6/-&;! /.(</(/1.! 1*!

'*)8/1<>!)H')*/6).(&;!@&(&E!!

U%)!:=!'*1(1-1;!&;>1!)H%/D/(>!'*16/>/.0!-16'<(&(/1.&;!')*21*6&.-)E!+.!(%)!

(36)

! YR!

(%1<>&.@>! 12! -&.@/@&()! @)>/0.>! 21*! &! 2&>(! >-*))./.0E! U%)! %/(>! 2*16! (%/>! /./(/&;!

>-*))./.0! -1<;@! D)! 2<*(%)*! >-*<(/./4)@! D5! *<../.0! (%)! '*1(1-1;! 21*! ;1.0)*! (/6)!

>-&;)>G! 1*! D5! >)((/.0! <'! >/6<;&(/1.>! /.! I%/-%! 6&.5! /.>(&.-)>! 12! (%)! ><D>(*&()! &*)!

';&-)@! *&.@16;5! /.! (%)! >/6<;&(/1.! D1H! &.@! <.D/&>)@! D/.@/.0! (1! (%)! &-(/8)! >/()! />!

)8&;<&()@!@<*/.0!(%)!-1<*>)!12!(%)!>/6<;&(/1.EVO_!!

N<*!2/.@/.0>!&;>1!><00)>(!(%&(!2<(<*)!)221*(>!/.!-16'<(&(/1.&;!).456)!@)>/0.!

>%1<;@! D)! 21-<>)@! 1.! /.-;<@/.0! D&-JD1.)! 2;)H/D/;/(5! &.@! /6'*18/.0! (%)! >1;8&(/1.!

61@);>!<>)@!/.!(%)!@)>/0.!-&;-<;&(/1.>E!+.!'&*(/-<;&*G!&!61*)!&--<*&()!@)>-*/'(/1.!12!

/.()*&-(/1.>!12!(%)!'*1()/.!I/(%!(%)!>1;8).(!-1<;@!).%&.-)!1<*!&D/;/(5!(1!'*)@/-(!(%)!

'1>/(/1./.0! 12! %/0%;5! -%&*0)@! >/@)-%&/.>! I/(%/.! (%)! D/.@/.0! '1-J)(! 12! @)>/0.)*!

).456)>E!

+.! ><66&*5G! (%/>!%"# 3%&%'(! (11;! >%1<;@! '*18)! <>)2<;! D5! %);'/.0! *)>)&*-%)*>!

21-<>!(%)/*!)H')*/6).(&;!)221*(>!1.!@)>/0.>!(%&(!%&8)!).1<0%!>(*<-(<*&;!/.()0*/(5!(1!

6&/.(&/.! (%)! '<(&(/8)! -&(&;5(/-! 0)16)(*5! @<*/.0! (%)! -1<*>)! 12! &! >%1*(! &.@!

-16'<(&(/1.&;;5!&221*@&D;)!>/6<;&(/1.E!!

!

4'%0&.'1$!'*,!40%5+,$!

9G#3%12&+-%("3#+"*#'0%-.0%+!

,/6<;&(/1.>! (5'/-&;;5! >(&*()@! I/(%! (%)! ><D>(*&()! D1<.@! (1! (%)! &-(/8)! >/()! 12! (%)!

).456)E! U%)! 76D)*! 21*-)! 2/);@! I&>! <>)@! /.! &;;! >/6<;&(/1.>K! 76D)*! 21*-)! 2/);@!

22QQ,SV"_{! I&>! /6';)6).()@! 21*! '*1()/.>! &.@! (%)! 0).)*&;! 76D)*! 21*-)! 2/);@}VY_{! I&>!}

(37)

! YP!

-%&*0)>!(%&(!%&@!D)).!@)8);1')@!'*)8/1<>;5"O_{G!&.@!21*!(%)!-%1*/>6&()!61;)-<;)G!I)!}

-&;-<;&()@! -%&*0)>! <>/.0! (%)! *)>(*&/.)@! );)-(*1>(&(/-! '1().(/&;! A\3,BC! 6)(%1@! &(!

TXgRLV"_q! ! &>! /6';)6).()@! /.! (%)! \3=,! >)*8)*EVVK! V#_{! 76D)*U11;>! "O! I&>! <>)@! (1!}

'*)'&*)! (%)! >(*<-(<*)>! 21*! >/6<;&(/1.>EV?_{! T5@*10).! &(16>! I)*)! &@@)@! (1! (%)!}

>(*<-(<*)>G!&2()*!I%/-%!(%)!>5>()6>!I)*)!-16';)();5!>1;8&()@!I/(%!I&()*!61;)-<;)>!

AU+BVB!I&()*!61@);CE!X/.&;;5G!`&+!_1*!$;! /1.>!I)*)!&@@)@!(1!.)<(*&;/4)!(%)!>5>()6>E!

U%)!-);;!>%&')!I&>!&!*)-(&.0<;&*!D1H!1*!&!(*<.-&()@!1-(&%)@*1.E!

U%)! >/6<;&(/1.>! I)*)! -&**/)@! 1<(! <>/.0! (%)! :=! >12(I&*)! `7:=! YEPEYQ_!

B*)>><*)!I&>!J)'(!-1.>(&.(!<>/.0!(%)!`1>)LT118)*!n&.0)8/.!'/>(1.!6)(%1@!I/(%!&!

@&6'/.0! (/6)! 12! ?O! 2>! &.@! &! @)-&5! ')*/1@! 12! "OO! 2>E! n&.0)8/.! @5.&6/->! I&>! <>)@!

I/(%!&!(&*0)(!-1.>(&.(!()6')*&(<*)!12!VOO!]!&.@!&!?!'>L"_{!@&6'/.0!-1)22/-/).(E!!M)!}

(11J! &@8&.(&0)! 12! (%)! 6<;(/';)! (/6)L>()''/.0! -&'&D/;/(/)>! 12! (%)! -1@)9! &! Y! 2>! (/6)!

>()'! I&>! <>)@G! .1.LD1.@)@! /.()*&-(/1.>! A8&.! @)*! M&&;>! &.@! );)-(*1>(&(/-C! I)*)!

-&;-<;&()@!)8)*5!(I1!>()'>G!&.@!;1.0!*&.0)!);)-(*1>(&(/-!/.()*&-(/1.>!r'&*(/-;)!6)>%!

3I&;@!AB:3C!I/(%!')*/1@/-!D1<.@&*5!-1.@/(/1.>!ABS$Cs!I)*)!-&;-<;&()@!)8)*5!21<*!

>()'>E! Z/><&;! 61;)-<;&*! @5.&6/->! AZ:=C! I&>! <>)@! (1! 8/><&;/4)! &.@! &.&;54)! (%)!

>/6<;&(/1.>EVR_!

B<*);5! 0)16)(*/-! -*/()*/&! I)*)! <>)@! (1! '*)@/-(! ).456&(/-! &-(/8/(5E! M)!

%5'1(%)>/4)@! (%&(! >(*<-(<*)>! (%&(! 6&/.(&/.)@! (%)! &-(/8)! >/()L><D>(*&()! -1.(&-(>!

*);)8&.(!(1!D/.@/.0!&.@!-&(&;5>/>!I1<;@!D)!&-(/8)E!X1*!(%)!])6'!);/6/.&(/1.!*)&-(/1.!

(%)! -&(&;5(/-! -1.(&-(! D)(I)).! (%)! 0).)*&;! D&>)! A&>'&*(&()! 1*! 0;<(&6&()C! &.@! (%)!

%5@*10).! 1.! ?L./(*1D).4/>1H&41;)! I&>! 61./(1*)@! @<*/.0! (%)! >/6<;&(/1.>! &.@! (%)!

(38)

! Y^!

@/>(&.-)! b! VEY! c! I)*)! '*)@/-()@! (1! D)! &-(/8)G! 1(%)*I/>)! /.&-(/8)EYOK! Y"_{! ,/6/;&*;5! 21*!}

$;&/>).! *)&**&.0)6).(! 12! -%1*/>6&()G! (%)! @/>(&.-)! D)(I)).! (%)! (I1! -&*D1.! &(16>!

(%&(! I1<;@! 21*6! &! D1.@! /.! (%)! '*1@<-(! A$^L$RC! I&>! 61./(1*)@E! =)>/0.>! (%&(!

)H%/D/()@! &! (/6)L&8)*&0)@! $^L$R! @/>(&.-)! b! VE?! c! I)*)! '*)@/-()@! (1! D)! &-(/8)G!

1(%)*I/>)!/.&-(/8)EY^_!

!

G./%"%-%("3#

U*<)!'1>/(/8)9!>/6<;&(/1.!i!&-(/8)!7`=!)H')*/6).(!i!&-(/8)!!

X&;>)!'1>/(/8)9!>/6<;&(/1.!i!&-(/8)!7`=!)H')*/6).(!i!/.&-(/8)!!

U*<)!.)0&(/8)9!>/6<;&(/1.!i!/.&-(/8)!7`=!)H')*/6).(!i!/.&-(/8)!!

X&;>)!.)0&(/8)9!>/6<;&(/1.!i!/.&-(/8)!7`=!)H')*/6).(!i!&-(/8)!

,')-/2/-/(59!'*1'1*(/1.!12!(*<)!.)0&(/8)>!(%&(!&*)!-1**)-(;5!/@).(/2/)@9!

,')-/2/-/(5!i!t!(*<)!.)0&(/8)>g!At!(*<)!.)0&(/8)>!u!t!2&;>)!'1>/(/8)>C!

,).>/(/8/(5E!'*1'1*(/1.!12!(*<)!'1>/(/8)>!(%&(!&*)!-1**)-(;5!/@).(/2/)@9!

! ,).>/(/8/(5!i!t!(*<)!'1>/(/8)>g!At!(*<)!'1>/(/8)>!u!t!2&;>)!.)0&(/8)>C!

`)0&(/8)! '*)@/-(/8)! 8&;<)! A`BZC9! '*1'1*(/1.! 12! '*)@/-()@! .)0&(/8)>! (%&(! &*)! (*<)!

.)0&(/8)>9!

! `BZ!i!t!(*<)!.)0&(/8)>!g!At!(*<)!.)0&(/8)>!u!t!2&;>)!.)0&(/8)>C!

B1>/(/8)! '*)@/-(/8)! 8&;<)! ABBZC9! '*1'1*(/1.! 12! '*)@/-()@! '1>/(/8)>! (%&(! &*)! (*<)!

'1>/(/8)>9!

(39)

! YQ!

"(6*+710,8090*%$!!

U%)!&<(%1*>!(%&.J!:&*/)!7*5!21*!%);'!I/(%!(%)!6&.<>-*/'(E!!

(40)

! VO!

!

:'#10!;<=>!3+9?'&.$+*!+@!0A?0&.90*%'1!&0$-1%$!7.%5!42!?&0,.(%.+*$!@+&!%50!B! CD!,0$.8*$!.*!%50!%&'.*.*8!$0%>!B*)@/-(/1.>!>%1I.!>%&@)@!&*)!-1**)-(E!`=!i!.1(! @)()*6/.)@G!7!i!&-(/8)G!&.@!+!i!/.&-(/8)E!H'+->!I)*)!*)'1*()@!/.!B*/8)((!.-#+&8!"O_! !

!

q!U%)>)!).456)>!&*)!&-(/8)!D<(!(%)/*!H'+-!-1<;@!.1(!D)!@)()*6/.)@E! 20$.8*! E('@@+1,!

FG2H!)2I! !"#$%F$<=I! G&+%+(+1!=!

G&+%+(+1!

;! G&+%+(+1!J! G&+%+(+1!K!

T_L"! "01*! +.&-(/8)! +! +! +! +!

T_LY! "01*! `=q! 7! +! 7! 7!

T_LV! "01*! OER^! +! 7! 7! 7!

"7?VL"! "&?V! +.&-(/8)! 7! 7! +! +!

"7?VLY! "&?V! OEO"Y! +! 7! 7! 7!

"7?VLV! "&?V! OEO"?! 7! 7! 7! 7!

"UTXL"! "(%2! +.&-(/8)! 7! 7! 7! 7!

(41)

! V"!

!

:'#10! ;<;>! E-99'&L! +@! %50! 42! &0$-1%$! @+&! %50! CD! ,0$.8*$! &0?+&%0,! #L! /M%51.$#0&80&!&$%#'>#_!_{`7G!.1(!&'';/-&D;)}_>!!

!! !!!!!!!!! ! !! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

! N+!42! G&+%+(+1!J! G&+%+(+1!K!

t!(*<)!'1>/(/8)!@)>/0.>! ^! R! #!

(42)

! VY!

:'#10!;<J>!!G&+%+(+1!J!&0$-1%$!@+&!%50!C09?!01.9.*'$0$!#L!/M%51.$#0&80&!&$%#'>#_!!

20$.8*! E('@@+1,!!

FG2H!)2I! !"#$%F$<=I!

3'%'1L%.(! ,.$%'*(0!,!

FOI!&_!

G&0,.(%.+*!D!

CDPQ! "&?V! OEYQ! VEO#! 7!

CDRS! "W-;! OE"R! YE^#! 7!

CD=S! "&?V! OEOYQ! YE?Y! 7!

CD=P! "(%2! OEOYY! YE^R! 7!

CDSR! "(%2! OEO"^! YEP#! 7!

CD=T! "(%2! OEOOR! VE"?! 7!

CDT=! "%R"! `=q! ?EO?! +!

CDR=! "&?V! `=q! RE"?! +!

CDS=! ")/H! +.&-(/8)! #EQP! +!

CDS;! ")/H! +.&-(/8)! #E"R! +!

CDSJ! "(%2! +.&-(/8)! ?EOV! +!

CDSK! "(%2! +.&-(/8)! ^EV#! +!

CDSP! ";D6! +.&-(/8)! VE"R! 7!

CDST! "(%2! +.&-(/8)! ?E""! +!

CDSB! "(%2! +.&-(/8)! #EOR! +!

CDSQ! "(%2! +.&-(/8)! VEYV! +!

CD==! "&?V! +.&-(/8)! YE?V! 7!

CD=;! "#^;! +.&-(/8)! YEQY! 7!

CD=J! "(%2! +.&-(/8)! ""E#^! +!

CD=K! "(%2! +.&-(/8)! #EPR! +!

CD=R! "(%2! +.&-(/8)! ^E#?! +!

CD=B! "&?V! +.&-(/8)! VEYY! +!

CD=Q! "8O#! +.&-(/8)! PEPP! +!

CD;S! ";D6! +.&-(/8)! VE^R! +!

CDJK! "8O#! +.&-(/8)! ?EQO! +!

CDJP! Y/4W! +.&-(/8)! VEPQ! +!

CDJT! "(>.! +.&-(/8)! VE?V! +!

CDJR! R-'&! +.&-(/8)! PE?R! +!

CDJB! ";D6! +.&-(/8)! VEVR! +!

CDJQ! "&?V! +.&-(/8)! ?E^O! +!

CDKS! "@-Q! +.&-(/8)! VE##! +!

CDK;! "/0>! +.&-(/8)! VE?Q! +!

CDKP! "8O#! +.&-(/8)! ?ERR! +!

CDKT! "8O?! +.&-(/8)! ^E"V! +!

CDKR! "@6F! +.&-(/8)! YER?! 7!

CDKB! "1'5! +.&-(/8)! RER"! +!

CDKQ! "@66! +.&-(/8)! RE?P! +!

CDPS! ";D;! +.&-(/8)! #E^Q! +!

CDP=! "'//! +.&-(/8)! YEQV! 7!

(43)

! VV!

CDPK! "W-;! +.&-(/8)! YEP"! 7!

CDPP! "/0>! +.&-(/8)! RE#Y! +!

CDPB! "IDW! +.&-(/8)! YE#V! 7!

CDTS! "W<;/! +.&-(/8)! VEO^! 7!

CDT;! "2(H! +.&-(/8)! YE^^! 7!

CDTJ! Y2'-! +.&-(/8)! REP#! +!

CDTK! "(%2! +.&-(/8)! VEOR! 7!

CDTP! ";D6! +.&-(/8)! VE#Q! +!

CDTT! ";D;! +.&-(/8)! REVQ! +!

CDTR! ">"@! +.&-(/8)! YEQY! 7!

!

`=G!.1(!@)()*6/.)@E!

q!U%)>)!).456)>!&*)!&-(/8)!D<(!(%)/*!J-&(!-1<;@!.1(!D)!@)()*6/.)@E! &!_{78)*&0)!-&(&;5(/-!@/>(&.-)!6)&><*)@!/.!&!"O!.>!:=!>/6<;&(/1.E!} D!_{7!i!&-(/8)!A/2!@!b!VEYO!cCG!+!i!/.&-(/8)!A/2!@!e!VEYO!cCE}YOK!Y"_!

(44)

! V#!

:'#10!;<K>!!G&+%+(+1!J!&0$-1%$!@+&!()%+',!(5+&.$9'%0!9-%'$0!',!.%$!==K!$.810! 9-%'%$!&0?+&%0,!#L!U'$$.1'!&$%#')YP!

4-%'*%! !"#$VC4! F4<=_!$<=_I!

3B<3T! 2.$%'*(0!

FOID_!

WK<3J<3K<W=!

2.50,&'1!"*810!F°I! G&0,.(%.+*!&!

=D34!FX:I! "EVO3uO?! VEVY! L"VQEV! 7!

"J;E! YE"O3uO?! VEV"! L"#OER! 7!

"J;:! "ERO3uO?! VEVQ! L"VPE"! 7!

YJP)! "E?O3uO?! VE#P! L"Y#ER! 7!

URZ! "E#O3uO?! VE#Q! L"YVE#! 7!

UR)! "EYO3uO?! VE##! L"YQEY! 7!

)B=4! "EOO3uO?! VE#^! L"Y^ER! 7!

YBP)! "EOO3uO?! VE#^! L"YYEQ! 7!

)B=U! ?E?O3uO#! VERV! L"Y#ER! +!

YBP3! ?E#O3uO#! VE#P! L"YPE?! 7!

YJP4! ?EYO3uO#! VE?O! L"Y"ER! 7!

YJP3! ?EYO3uO#! VEPV! L""VE"! +!

URY! ?EOO3uO#! VE?Y! L"Y"E^! +!

UR4! #E#O3uO#! VEV#! L"#OEY! 7!

YBPU! #EVO3uO#! VE?#! L""?EQ! +!

YBP/! #EYO3uO#! VERP! L"""EQ! +!

YJP"! VEQO3uO#! VEQ^! LQRER! +!

YBP[! YERO3uO#! VER^! L"OQE?! +!

YBP:! YEYO3uO#! VERP! L""VEQ! +!

YBPZ! YE"O3uO#! VEQ"! LQ#EP! +!

YJP:! YEOO3uO#! VE^?! L"O?E?! +!

2KB3! "E^O3uO#! VEVQ! L"VVE"! 7!

YBP4! "E?O3uO#! VEV"! L"V^EP! 7!

YBPC! "EVO3uO#! VEV^! L"VVEP! 7!

YJPU! "EVO3uO#! VEV^! L"#"E^! 7!

UR:! "EVO3uO#! VEP?! L"O#E#! +!

YBPN! "EYO3uO#! VER"! L""?EO! +!

(45)

! V?!

UR3! "EOO3uO#! VEVP! L"VPEQ! 7!

2KB\! QE^O3uOV! VEVP! L"V?ER! 7!

)B=Z! ^EPO3uOV! VEV"! L"V^E#! 7!

2KBN! PEQO3uOV! VEP"! L"OPE?! +!

2KBU! PE"O3uOV! VEV^! L"V?E"! 7!

"J;3! `=q! VE#"! L"#"EQ! 7!

)B=3! `=q! VE?"! L"YRE"! +!

"J;]! `=q! VEPV! L"O^EV! +!

"J;)! `=q! VE^R! L"OVE^! +!

)B=X! `=q! VEPV! L"O^EV! +!

YBPX! `=q! VE?Y! L"YPEQ! +!

"J;Y! `=q! VE^Y! L"OYEY! +!

)B=Y! `=q! VE?"! L"Y#E#! +!

"J;2! +.&-(/8)! VE?^! L""QEY! +!

"J;D! +.&-(/8)! VEVQ! L"VPER! 7!

"J;Z! +.&-(/8)! #EVQ! L^VEY! +!

"J;^! +.&-(/8)! VEVR! L"#RE"! 7!

"J;C! +.&-(/8)! #EOV! LQVE"! +!

"J;U! +.&-(/8)! VE#R! L"Y#ER! 7!

"J;4! +.&-(/8)! VER^! L"O^EP! +!

"J;N! +.&-(/8)! VE#V! L"YQEQ! 7!

"J;G! +.&-(/8)! VEQ#! L"OPE?! +!

"J;\! +.&-(/8)! VERO! L""?E"! +!

"J;/! +.&-(/8)! VE?^! L""RE?! +!

"J;X! +.&-(/8)! VE^^! L"O"E?! +!

"J;[! +.&-(/8)! VE?#! L"YYE#! +!

2KB"! +.&-(/8)! VERP! L"O^EO! +!

2KBD! +.&-(/8)! VEYQ! L"#VEY! 7!

2KBZ! +.&-(/8)! VEV^! L"VPER! 7!

2KB]! +.&-(/8)! VEPY! L""OER! +!

2KB^! +.&-(/8)! VE?Q! L""RE#! +!

2KB)! +.&-(/8)! VEQP! LQOER! +!

2KBC! +.&-(/8)! VEVP! L"V#EQ! 7!

(46)

! VR!

2KBG! +.&-(/8)! VEPY! L"O?EP! +!

2KB/! +.&-(/8)! VE#?! L"Y?E^! 7!

2KBE! +.&-(/8)! VER#! L"OQE"! +!

2KB:! +.&-(/8)! VE#V! L"VPEP! 7!

2KBY! +.&-(/8)! VEVP! L"V?EP! 7!

2KBX! +.&-(/8)! VEVQ! L"V#EO! 7!

2KB[! +.&-(/8)! VEV^! L"VVEO! 7!

)B="! +.&-(/8)! VEP^! LQQER! +!

)B=2! +.&-(/8)! #E"Q! L""OEV! +!

)B=D! +.&-(/8)! VE?Y! L"YVER! +!

)B=]! +.&-(/8)! VE#V! L"V?E#! 7!

)B=^! +.&-(/8)! VEV?! L"V^E?! 7!

)B=C! +.&-(/8)! VE#"! L"V?E^! 7!

)B=N! +.&-(/8)! VEVY! L"#YEO! 7!

)B=G! +.&-(/8)! #EOY! LQ#EV! +!

)B=\! +.&-(/8)! VEQ"! LQYER! +!

)B=/! +.&-(/8)! VE?R! L"V"ER! +!

)B=E! +.&-(/8)! VE#^! L"YQE#! 7!

)B=:! +.&-(/8)! VE#^! L"V"EV! 7!

)B=[! +.&-(/8)! VE#P! L"YQE^! 7!

UR"! +.&-(/8)! VEPO! L"O^E^! +!

UR2! +.&-(/8)! VER#! L""VE^! +!

URD! +.&-(/8)! VE?R! L"Y"EO! +!

UR]! +.&-(/8)! VE#"! L"#YEO! 7!

UR^! +.&-(/8)! VE?^! L"Y?E"! +!

URC! +.&-(/8)! VEQP! LQOEQ! +!

URN! +.&-(/8)! VERV! L""YER! +!

URG! +.&-(/8)! VERR! L""#ER! +!

UR\! +.&-(/8)! VE##! L"YREP! 7!

UR/! +.&-(/8)! VE?R! L""PEY! +!

URE! +.&-(/8)! VERQ! L"""E?! +!

URX! +.&-(/8)! VE?Y! L"YOE^! +!

UR[! +.&-(/8)! VE#O! L"VRE^! 7!

(47)

! VP!

YJPD! +.&-(/8)! VEV^! L"#VE#! 7!

YJPZ! +.&-(/8)! VE?P! L""OEV! +!

YJP]! +.&-(/8)! #EO#! LQ"EQ! +!

YJP^! +.&-(/8)! VE#R! L"Y?EO! 7!

YJPC! +.&-(/8)! #EYQ! L"O#EQ! +!

YJPN! +.&-(/8)! VE^Y! L"OPE"! +!

YJPG! +.&-(/8)! VERR! L""VEP! +!

YJP\! +.&-(/8)! VE?V! L"Y"EY! +!

YJP/! +.&-(/8)! VEVV! L"#RE"! 7!

YJPE! +.&-(/8)! VEPO! L""#E?! +!

YJPX! +.&-(/8)! VERV! L"OQER! +!

YJP[! +.&-(/8)! VE#R! L"YQEP! 7!

YBP2! +.&-(/8)! VE#V! L"VOEY! 7!

YBPD! +.&-(/8)! VEV#! L"#"EO! 7!

YBP]! +.&-(/8)! VE?O! L"VOE"! 7!

YBP^! +.&-(/8)! VER^! L"OPEP! +!

YBPG! +.&-(/8)! VE?Q! L""?EP! +!

YBP\! +.&-(/8)! VE#V! L"YQER! 7!

YBPE! +.&-(/8)! VE#P! L"YVEQ! 7!

!!`=G!.1(!@)()*6/.)@E!

!!q!U%)>)!).456)>!&*)!&-(/8)!D<(!(%)/*!H'+-!-1<;@!.1(!D)!@)()*6/.)@E! D!_{78)*&0)!@/>(&.-)!6)&><*)@!/.!&!"O!.>!:=!>/6<;&(/1.E}!

(48)

! V^!

! ! !

!

Z.8-&0! ;<=>! C09?! 01.9.*'%.+*>! F"I!])6'! );/6/.&(/1.! *)&-(/1.! >-%)6)E! FHI!+@)&;! &-(/8)! >/()! 21*! &! ])6'! );/6/.&>)E!U%)! ><D>(*&()! />! @)'/-()@! /.! *)@E! U%)! @/>(&.-)! 6)&><*)@!/.!(%)!>/6<;&(/1.>!/>!/.@/-&()@!I/(%!&!D1HE!F3I!3H&6';)>!12!:=!*)><;(>E!T_L "!A0*)).CG!&.!)H')*/6).(&;;5!/.&-(/8)!@)>/0.G!)H%/D/(>!@/22<>/1.!12!><D>(*&()!2*16!(%)! &-(/8)! >/()! )&*;5! /.! (%)! >/6<;&(/1.E! T_LY! AD;<)CG! &.! )H')*/6).(&;;5! &-(/8)! @)>/0.G! J))'>!(%)!><D>(*&()!/.!(%)!@)>/0.)@!-1.21*6&(/1.!@<*/.0!(%)!).(/*)!>/6<;&(/1.E!!

"!

(49)

! VQ!

! !

!

(50)

! #O!

! ! ! ! ! ! ! ! ! ! ! !

Z.8-&0! ;<J>! G&+%+(+1$! J! '*,! K! 0A(01! '%! ,.$('&,.*8! @'1$0<?+$.%._0! ,0$.8*$>! B*1(1-1;! V! 0/8)>! (%)! D)>(! *)><;(>E! S1(%! '*1(1-1;>! &*)! %/0;%5! *)'*1@<-/D;)E! `BZ9! .)0&(/8)!'*)@/-(/8)!8&;<)K!BBZ9!'1>/(/8)!'*)@/-(/8)!8&;<)E!U%)!>(&(/>(/-&;!'&*&6)()*>! &*)!@)2/.)@!/.!:&()*/&;>!&.@!:)(%1@>E!=)(&/;)@!*)><;(>!21*!)&-%!@)>/0.!&*)!&8&/;&D;)! /.!U&D;)!YLVE!

(51)

! #"!

! !

!

! ! ! ! ! !

Z.8-&0! ;<K>! 31'.$0*! &0'&&'*8090*%! +@! (5+&.$9'%0! #L! (5+&.$9'%0! 9-%'$0>! F"I! \)&-(/1.! >-%)6)! >%1I/.0! (%)! $;&/>).! *)&**&.0)6).(! 12! -%1*/>6&()! (1! '*)'%).&()! I/(%!(%)!@/L&H/&;!(*&.>/(/1.!>(&()!@)'/-()@E!FHI!U%)!&-(/8)!>/()!12!@8#'(&%!-%1*/>6&()! 6<(&>)E! $%1*/>6&()! />! @)'/-()@! /.! /(>! @/L&H/&;! -1.21*6&(/1.! A5);;1ICE! $&(&;5(/-! *)>/@<)>!&*)!>%1I.!/.!1*&.0)E!n&>>/;&!.-#+&8YP_{!-1.@<-()@!>/()L>&(<*&(/1.!6<(&0).)>/>!}

>(<@/)>!1.!(%)!>/()>!>%1I.!/.!0*)).E!!

"!

(52)

! #Y!

! !

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Z.8-&0!;<P>!!2.<'A.'1!(+*@+&9'%.+*!+@!(5+&.$9'%0>!U%)!><D>(*&()!/>!@)'/-()@!/.!/(>! @/L&H/&;!-1.21*6&(/1.E!U%)!&(16!.&6)>!&*)!>%1I.E!n)2(9!@/>(&.-)!D)(I)).!$^!&.@!$R! />!>%1I.E!\/0%(9!@/>(&.-)!D)(I)).!$^!&.@!$R!&.@!&(16>!/.81;8)@!/.!(%)!N#L$VL$#L N"!@/%)@*&;!&.0;)!&*)!>%1I.E!!

(53)

! #V!

! ! ! !

!

! ! ! !

! !

! ! !

Z.8-&0! ;<T>! :&'*$@0&'#.1.%L! %+! '*+%50&! &0'(%.+*`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

! ! ! ! !

"!

(54)

! ##!

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Computational Enzyme Design