#$"" %9 , $"% $"!"#!#, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 4 3,3, #!!$#!#, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 4 3,4, "!$"!+!#(#%$!#,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 5 3,5, "$") %"#"!$"#!#, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 8 , &% #$ ",,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 9 ,# (%$###!#,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ; 5,3,# ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ; 5,4,"$"#$#"#% # ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 32 5,5,$#" ###.#/ ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 34 # ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 34 !, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 35 5,6,$#" ### ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 36 , ##!#%##"%$,"$"#$#, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 3: 6,3, " ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 3: 6,4,$ ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 44 6,5,%!"",,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 47 6,6, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 4: 6,7,-',,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 4; 6,8,- $ ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 53 6,9-" ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 53 ,%$##%$,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 56 3 !" #1 &!" # " ! !#!"! " %" ! ! " " ! % " ! ! ( ! #"#!" " ! $! "" "# , " "+!# ! # &!"# + # # " !! # ! !# !" #"# # & !# " %! ! " , !" !#! ! % ' # " ! # !" !! # !"# " % " &+#"!", $!# ! " + .210 ! !+ " +#" # "! %!# %"!"'!" !%! " "+!" ! # ! "! #! &, # !" " ! " ( # "+! # !""!#"! &-" + " #+ !! " ' #-, ! " ( ! !+ ! !# " #!" !"!"%,!+!! %#!#" "-!" !"-" "#" +##'! "! !""%+!- ,!!#!+!" ! "! ! # " !# &" !# #-+ ' ! ' - ,#"!"!"! ! !+! " " ! !+ ! " ! ' , #!"!!! ""!"!!+! !. '/, / ! "3 Leu-encefalina YGGFL Dinorfina A 1-17 YGGFLRRIRPKLKWDNQ Met-encefalina YGGFM Endorfina YGGFMTSEKSQTPLVTLFKNAIIKNVHKKGQ Neoendorfina & ! ! ! !) $ 0 & 1) ! " ! ! #) "! " %!-!, ! "! " " "! " " & " " , !"!" " ! ! "!! !"!"" ! !" " ! ." 0/+ " ! % " " " ! " 1 " " ! , !$ !"!"! ! &%" " !$ ! !! " , ! "" !)"" & " " !", % ) ! ! !! ! " ! & + -)"$"-)!-& !#!" ! !$!*-)" & &*&-!)" " , % !"$ &" ! !! !$ ) " " " % ! " ! $ ! , $ %! !"$!!$ !$ " ! &! ! "' ! * ) " " ! ' " 2 ()'##' $*#@ (!'# ()!! !*# ! *! ! )*# %#' #)'# ()!)#5 ! !) ( !'#! )'( )%#( '%)#'( #%#( ! *!$! -()! *! # %*()# (),#μ , %#' #'!3,%#')#/#!3. %#':959=@2(!()+) #!#( #!(' #. ! # # *! '%)#' #%#2 ! %') # &* (* ), !# ( #&* %#' !)#!() !#-#!2 # # #*'' #! #( ( '%)#'( #%#(5 ! )'' )%# '%)#' #%#2 &* ( !# !$ ( (*'$ !/' $! ( !!( ! ,(# '!) ')$!2 #!2 #!)''# # &* #*'' ! * 2 %#(!*!), .#'&* #'!5 ! !/# ( %'#%( *!$! #( '!)( %%)#( #%#( !)#( () # !)# #! #( )'( '%)#'( #%#( (')#( %' )')' ()'&*'#!(-()!!)'#(5 %*'&*'%)#'#%#%'(!)*!)!%#'(!!( . ! %#' !#'!2 # &* (*' &* !! ( *! !# !$!# ()'%)#'5#(%%)#(',#(%'#!#'!-!*!%#)!)),(#' '%)#' , !)'( &* !! %'(!) *! !2 # &* (*' &* #( %%)#( ',#( %'#!#'! %*! (' #( !*'#)'!( (#'( !$!#( &* )+! (#' '%)#' #%# . '%)#' #%# μ %'(!) *! ) ! %#' ( !# #'!( .2 ! !#' '#2 %#' ( !!(2 # &* (*' &* ( !# #'!( %*!!)'#!'#!()'%)#'!#!#!((#$(5! !)2!#'! (*!%#)!) !))!)#'%)#' # #μ,%'#-*!! !#'%#' '%)#',#&*%!)%#(&*!)#(%''#(2#!!#'!( (*!!)&*!!#!#'!2!#'!(!#!$!#%' #('%)#'( μ. '), !) (% #( %%)#( #%#( (#' #( '%)#'( !)#( () # !)# !# %' )# (* # %) ')'/$! ' #$3 %#' #2 ( ! ("# *! (' # %*()#( (!))#( #! ! #)!' *! # %*()# &*2 +! #!(',!# % !( *(2 !# %#( ')'()( ),(5!)')##(#(# %*()#((!))#(&*(!(''##%# #()' 2 &* ( *! !## ( !!( *. ()'*)*' ( 6;6 !!!=6 !#>6!!.)+# #*!#!()μ ) !)(),#22*!#!() (),#*.()'*)*'()#' %#'*!$!#(%! !(46!;66 !>6!!2>92=AA.?B2>B<2(#!#!('#(# ##!()((),#(%' '%)#' #%# . %!# ()#( . #)'#( # %*()#( ( #'# '!' #( )'( )%#( %'!%( '%)#'( #%#(2 &* %'(!)! %'#%( ' #$( ' !)()!)(5 = *+)"%"%) &,"%B "+)!$%" "+%)!$ @;3?CC AD3@D> %) =;?3?CC μ %)!$ "%/%$!$ $+$!"% $%#%)!$< $%#%)!$= %*"+!.% "%/%$ !')$%)!$ %*)'+%)*%'!%!*')*$+$,$"+!$!'%)"%*%$!*+*33 "+%)!$ 0"$+%$!*+$"+)!$%"3"%*,"**,$$%$#$%)!$!"%*)'+%)* μ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μ &()"* +" * " &$( $")* &&*$ 4 !$(" / )+ !*$ *$ *-$ !$("6A ++(%"$4 ) $!$ &$( $) "*$")*)/" $.$""5 !$("4)"!($4))+" $)(&*$() /, +"'+$""5)*+$)(!$ %$)*!")+(" .)*")+*&$) (&*$() μ : μ</μ=4)"$)*, *!$ '+&()()&$&( !$("5 "*$")*" $.$"0")!& &( "%" $)(&*$()μ "μ</μ=4 )( )+*&$μ1)") " $.$"0"4!"*()'+ )+*&$μ=)")") 5 $) &(!($) "*"*$) &( (*(0( !$ + (!"* $) (&*$() $&$) +($" "(+*+$)$)5 &+(%" &($*" $ &($*") ) '+ ) +"" $) $!&+)*$)$&$))-!&&$( !& $)+)*"))"*+( 0"*)&()+ )$ + 0%" '+ '+ &(( & +"%" "$) )&$)5 " +" )+" &($.!%"4 ) +* 0($" "$) !($) (*-!"* '+ ) +"" $- "*!"* (&*$( / &(!*" +" !$( )+!"*$ &($)$ &+(%"4 !) +)$*("*)!)+(*)" &($)$.*(%"/&+(%"5$($*( &(*4 "*(&*$()&()"*)" $)*$))*+$)(&'+#"( %" $"$*($)$!&$""*)&()"*)" ) + )4 $'+(&()"*+"&($ !$" 5 ," )4 ) $(($" &+(( &( !"* / ($")*(+( " !$ $) !!(" *&$ -)+ +") &($*") $" & +"%" "$) $&$)4 +"'+ &()"*" (")(")4>@D?4"+"*$&)$!$ + (5&(*()*)&($*")) ($""*"*$))+"(+"&$ &&*$'+&(!*($*"(+"$ $"+ %*$&( )(+* 0$$!$)$"")(+*"$)"$*)5)*$)+($"!&($+*-$)4/'+ $) $ $"+ %*$) $*"$) (" !)$ "($) $!$ &( )( +* 0$) $!$ )$")5" ,"$)$" '+)*&($!"*$*+-$.*$4)$")+%) (+" '+ $ &($*" 7$&$ "" )$" !$ + 84 '+ &()"* $!$ $ $" )+&(! "!+"$ $+ ") / ) !$ + ) )%" + (4 &($ ( 0( )*+$) *(")%" / +"%" "$6(&*$( ) $!&($% '+ "$ .)*+"%")&4)(*"$)$!$ (&*$(+)$5 )&+)4+("*#$)))+%)&+ "$)$( "*+( 0)*$)(&*$()/ &$) '+ $) *() *&$) "$) &$( (*($) (!$ %$) ) $(()&$"(" $" $)&($+*$)*()")("*)4+("&($+*$) &($)!"*$ *("*-$ +" ,"$ " $" ("*) .$")4 ) *(*( +" ," &($*" '+ ) !$ &$)*6 *(+$" !"*4 $ +" &($*" +/) &($&) +"%" ) !$+ )" !"* "*($")$"$*($)$!&$""*) + ())&$)5 " ) <DD=4 $) (+&$) "-)*$() " (" / " )*$) "$) $(($" $"( )!+ *"!"* &(!( (&*$( $&$5 !$) (+&$) +* 0($" +" "$* .&()%" $(" &(*( " + ( !+(" <;C6<@4 '+ .&() (&*$( $&$ " !/$( +"" '+ *$ "(-$)$ / ( $) A +,*"&"&* '-"&D *(,&*+ &(&+ μ 1 . &+ "&$+ + +"&$*&$ (&* " ( -$* "$&+ +",/&+(*"*(,&*&(& #*&+*&,/#$,:<?@C=9 1<A=9 ;8 " "&$ (-*& (&* #&+ *-(&+ *+-",' $,& " +-$*+5 1 +- $"++ &$*#' )-5,/#$,5&-$(*&,$)-(&+"+*,*+,+-$'$"$&+ "*(,&*&(&. -+,& )- (* /$, )- "&+ *(,&*+ &(&+ *$ (*&-,& $+ +,$,&+5 + &$,$-' &$ " .+)- "&+ *+,$,+5 ,$$& $ -$, )- "&+ &,*&+ *(,&*+&(&+(&*$+*(*&,$++#!$,+"1"&$&*(,&*.+5"*(,&* &(&μ++"'"$"2*-$$&,&$-$+&$)--&,$(&* #("$&&"&$-"',&++%&+(*,*"+-$"*(,&* .&*&,*(*,5 ""*(,&*&(&++"'#$*+-"-$&+$"2-$$&,$ -++-,(&+"*(,&*"+&#,&+,,$8 "&$'$ "&+ $+ )- &$ "&+ *(,&*+ &(&+ &$*#& )- (*+$,$ $,* + -$ ",& *& &#&"& $ +- +-$5 ,$,& $-"&, &#& (*&,8+,"#&#$,&+$"&*&*,*2*"&+,*+,(&+*(,&*+&(&+ $$#"+0(*#$,'$:*,'$5*,5&1;1,#$$"+*-#$&8 $,$,* "#* " &"&* +& -$ "+ .+)-+ #+ &$+,$,+ $ " +* -#$&8 &+ (*&-,&+ */&+ " #(&" :(/* +&#$*-#;5 +$& " #+ &$&&"&(&,#$$&#$&#&$-#5+$#("&+,#(&+*#&,&+8 $,*(*,'$,&+*)-&"'&+$,-&++#-51+"+"**-$& 1'$+#(2*&$-",/*#(&"+(*+--+&#$"5-$)-(*)--$" $,--#*5"*&*A>>>'B>>>%&+$,+*+,&8++,2&$*$, &5 +- -,"2'$ + (*&(' "+ -",-*+ " -*&( #,**$ 1 " *+,& +8 $ " #(*& (& + *&$ ,&+ +- -+&6 +5 $ " ((*& *+ + *.$$ ,*,#$,&+ #("$& $-#*&++ +-+,$+ $"++8 $ 0/&$+ *"2+ $ (*+""'-$(((*"&(&$*#)-,$"+"*&$5 ?@>> 8 8 *& -*&$ "&+ *&+ "&+ )- +$,,2*&$ " &$&#$,& " &"&* 1 +-+ *#&+6&"(*&(("*&(&,$-$&*$"$&7&(&+E!-&8&#*& ,$+-&* +$"+"&88"-+&-$*&(*&/$$,(,&(* "#$*"+-*#$,&5)-+$,&&#&&(&8#+5('*,+1+-++(-"&+5 )--$*&$+--,"2'$$"*$,-5-,"2$(*"#*"&"&*&*,2 +- 1 *2 #$*&* & " !-& " &*#*5 +$& +, .",#& -,"2& &#& $"+&5$+,+&$*-5$"-+&5(*(*,*"-,$+$*#&+,*#$"+8 - -+& + 0,$' " /"2'$ *&#$5 $ " )- " &+ " +-%& :&#$-+; + " +&" *(*+$,* &$ -$ $&* & -*$& ""$& (+-"+ #(&"+8 " #+#& #(*&* D ,-+#'#'+ (.#'F ..,-'.-#4.%(+$.#$,-+#')'83+(%, *.##('%,.$+$, FD ')' ).+' # : % # ,#' : :8 #%'8 *. ".%-' '% )(+-, -.1' +% %#.%%#,++'##'#$%8$%,-+')')+#1+#','#'+,4 ' (#',8 , '$' # ++8 ,%' )+'#$%- ,- # )+$+ .,' $%# #, $)'#, %#$%+#.,$8$'##++$%8.,#%-+'3')' )+'#'+,%-%,',831%)+').%,..,'%#,#$#,#':+,#8 % # .# # +$') 3( % ,.,'8 +#,' )+'$'1( # .,' .% *. '%-% ')'#*.%'$%(#.%'8#%'#;)+#%$'+-#<3.3' .,',2-%(#'#+'-'.+')%-+#%#,#':%#,#',-%#, .+, '$, 3%$ % %#-++ 3 % #$'%- % '#%8 *. '%,+% # ')''$'.%,))%.%1+,#)+-'',#',$#,: # )' , ".%-' '% #', )+'.-', +1', # +$%-(% #'(#8 )+'#$%-.%#,)+$+,,.,-%,'%+-+ ,-,),'-1,*.#'$+ $)#( '% %, #/',8 $, %, $',9 , 8 ".%-' ,. .,' , ,++'##( )+##$%-,..,':'2,-%++%,,-(+,*.$%'%%*.#')')+'. (% ,- # ,#' 8 .%' , ,+% #', )+$+', ,', )%% , 3 ), *.: % # ,#' 2,- .% %' ,,-$ '$+# #+'+ # ')'8 *. ,%%(#%'$%.++#)'%-+%%#-++83*.#.,'')' %%, '%1+-'%.%+1)+'#$93%%#-+++'$/%,..,')+# '#'+ $.#,8 #', (#',8 %#.,' , , -'', #', , 3 %&', )*.&', )+ $%-%+#',*.-',: %BGAE8.%+$.-'#$%8++::+-0+%+8,#()'+)+$+14# )+%)# '$)'%%- # ')'8 .% , ##% '#'+ #%' $+##%-' # *. %'$%( '+% % '%'+ '+'8 ', +' # ,.&': $', ,-+ *. # $'+%,#)+$+,.,-%*. $).+,#%-'$'#)+%)'-1' .%)+'.-'%-.+#: $'+%+)+,%-)+'2$$%-#BDJ#),'-'-##')': #')'8$,$'+%8'%-%,-.%CDJ,.),'%##',:'%#-$)', ##+'%,#+'-+','$)'%%-,#')''$'#' %'$-#$'+%=A:DJ%),'# ')'>8 $)'+-%- ,.,-% '% )+'), %--., %, 3 #+$%- -1,9 - % =$-#$'+%> *. )', -', '%1.#,1%-, )+' %' %#,', =BJ>9 ))1+% '% #+, )+'), +#"%-, $.,.#+, =BJ>9 3 %',)% -$% '% )+'), %--., %,:=BAJ>: $'+% . %'+)'+%', % .% +% 1+ +$', # #% # )/#')+#-+-$%-'#'#'+83/%'3% ,#%#,'#(%%,', '#'+$.3%-%,'3'$'++%-)+#1#.(%%.1',)+'.-',%#,',:'% # %1%(% # "+%.## )'+$8 # .,(% # .,' # $'+% .$%-( '%,+#$%-'%1+-%',%+'$%#.,')+)'%+%-:'$'#$'+% + -% -1 *. # ')' 3 2,- .% 3 )+'.)(% )'+ ,., -', %,#,8 , )+'( # /,*. %.1', '$).,-', *. ++% ,-, +-+ ,-,9 , 8 %+ +,+ % BGFD ,++'##( # +' %8 .% +1' -#' *. ## '% $, G #$"" %: ##$ "'#0 #$ % "* " "# "%$ )"- #%$'0 %#$ " ##%#'"$!% " # " #$$'#" %!% #% # %#$" # # %$ " * # 7<;9 36-8: 1 $$#4 7<<7 38-<9 1 $$#4- $' # $"#%) "#%"#$ ###""#%0 #$ #% # "$# %##0 $%# " # ) $"# "## #%- # # "- "% !% # $##$#$# "#$-##$"#)$# " "$# "#)"#0 !% $ # $ "$ $%- # #%$# "%# "## ) " #- # $%" !% "% # %##$$"##%##) $ "#0 ##)# "###$"$$"#%" "* % #%# # %$ " ) " #$# "#- %) "# #%# # ) #%# $# ##- #" $#""$#" 0 %!%(#$"$#"##"#"# #-#% %$ '#$ "$)$'$"#%%#- #""/ 4 #$# %"##$%$$#"" $"#μ; 4 #$#2$#$#- # # #$# #" " $"# " !% " % $ #$ " %# $#$ #" " $"# μ0 $!%#$$ "# "%*- "" #"%#$ #" $"#. 4 #$# "#/ # % $' $"# " !% # #$# %"#- % "$"#$#$# "##. 4 (#$- "&$-%"% "# "#" $"# # " !% " $' $"#0 # $#$# %"# !% "#$)" "" $"# μ "$#"" $"# . < %&$ $ !' 6 $ &, '"$ $ * $ ' &$* & '& $ & , & * * $ $ ) $ *&$ "$ " * %' &)! $"& $% μ "$ ' %/ ' $/ "$%!$%"$& $/%&$& /(%%/)!& %+$&!'$$1 #' &)!$"& $%μ $&)$& %%&$'/)"$& /' %$ )& "'%& #' & % % % " '$ % % & % &$% % %1 $ % #' % + #' &$ '& & $ #' " %&$! $"& $ % " %0 ) #' % %$$ % "$ & % % & %/ % #' & % $"& % % "$% $% 2%/ "$%! $%"$& $/ %! " &%!31 "$ ' & $$',&$ %$ % " %#'&)'% &" $"& $" $ #'/ ' % %& &$% %&$! ' %& μ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μ + ( $/ % $ + " $ #' %' ! % % $ + & && & , " $ * / #' "$ & %&$ #'"$&" &$ %% % &)! %%&%%$ & $ %+ $$$ %2 +$ "$%&'& % '+$ $ $ #'%%' $" $$"& $%μ; %& %'&& % &$' ' $ $ & "$% $ % $ 2 % $ % "$%& ! &&'%/ "$ ' %&$& / (%%/ )!& %/ $ %&/"$ $ "2'& % "'%$(&%% % &"$& % % &)! $"& $% "$ ' % "$ ! % $ #' "$ ' " $ % %&% μ; % + #' &$ '& %" % $ %%&$'" /#'"'$$'! %&"$'% & %& % $ $"& $% μ.. '& %'% & % '+ "$%! $%"$& $/ #' % " " $&&/"$& )"$& %&) 2$ /"'$'$ (%%/ )!& %/ $ / )$& %/ % + "%' ' %2 '#' "' $ "$ '$ $ "/ %& % $', % $ % %&% "'$ % $"& $%μ, *"'%& %"$& &$ $2 %&$'" %'+1"&, %%! $/ 8 )% % " && #' $/ + #' % ' & % %!$ %/ &#'$ + '& %' 7 " $ #' %& &$ $ + $& $ 2 '& $ + '/ % + $ " & % #' "&, +/ 66 '(&""& #)": '" ) 1 ' - %) ( & ) ( %) $&") ''"' ("' $'"("'-&"'("'&"+')&''!"' (&"& (2 " '('$&'2)$& "& $"') $"( '86396+'-"& %)"& 1") ( (') $"&&$("&'μ, ) %)( ' ) &$("&'.) (&# " "'($"'&$("&'')-&$"&"%)1' '$&")$ '' (1-' &"'( (& $&&-' "& ( '2 '( )&( # "' &$("&' "$"' ,$ %)1 '" (",# )1 "' (" '(' "" "," 1 (* " )( " %) '&""(&''& # $ (2 "' ("' "(&' %) "$! '(&# )$& "& 1 '" "' '&("'$&"'&"' (&"& (,$)'("') %) ) "''"'1"" $&'# &'$&("& " &"$ 1 ') $&# ' ' ( - '1 $&"). ' ("' '#&"' "' &) ( (1 ') (" '(& ( ' "& - &.("'&"+')&'2 $&$# "''()"'""&"'"'4 # )"&# 1'" ' "' &+"'1 '()"' "+"' ($" "1 (&" " %)"5 $ $&($# +&''(&)()&' )&'1'"'(& '$&&"''('." ''"("' '"&' "&(. &&1 ) " "' )' $&($ '"' ")("&"' )- +&'"'1-'( "(""(&"'''('&)"&'2 ''(& ((& '(' '# ""&"'''(& " '&' &+"''($"-1%) &+ ''('"&'')'$ 1(&+'+' '$ "3('1'$ "3&()&-'$ "3' 1'"""(&'+'""''$ "3 ' - '$ "3&+"('1 '( ) *&" &" ' (&" " " - " )- " ("1 ')'( &' $&))(1 &# $&&%)1 "&# &()& $&&%) - *"' ) &"'(& + (&2 '1 ' $'' (" $&"-( "' '( (' &'1 "" & ' '(+ ') & $&(1 #)" &" (1 ." ' #)" ($"&1 ''( " " $"("2 "' "$"' (* ( (" '"& ''( & ( %) + "&# "$(+ "" '"& ''(& (%)"" (&"1-&) (+' ($"&'('+'1$ " &# ')'( 2"& ''(& (&' "&(.1' "- )" )-'(&)()&'""')'( &'$&))(1")'&))'1')&))'1 *"' #&3)'1 *"' )' & - +&"' *"' "&# &()& )&2'(''(&)(& ''# "&# "$(+ )'$ 2 "'"$"'(+ '" ," ',(("&' (&')'( &'$&))(- "' *"'& )&"'(&+ (&2' )&" '&" ( ')+." ' )&" ' "$(+' ' '111-''(''$ "&'1' 78 '(&""& #)": %) 1 )- " )&" ' '$ "(' - '$ "&&()&'4 ) &"'(& + (& ,'( "' '' )&" ' $"&( (' $& (& ''# ""&3 ' )' -')'4 '$&&'( (& ''# "$(+-'')'( '"$' $ ') (+# 2 ' ') ' (& ''# $)'" ""&"'" - '" (+'$"&'')'( '"$'1 "&( (1' "$"& # ) '" ("&" %) ' &" '"& ' $"& (& )&" ' %) " ( 1 %) '" ''')'4 "' "$"' ( (* + " - "&( " '#" &) " ' ' '()" ""&"'"1 ' " ( ) " $&$# ""& - (" " '&" )'("'"'"1')'(()- "" )'" "'" '$"&) ' '# $ (&%)') '(&# "$"'4 ,'( ) " ' '" & ( $& $(& )'" "$"' (&( (" ""& ( '" &(& )"1 (&)('"' $"& 41 " $& ""& '"" $&"'"' $"( ((& '"" '" &4 ' $( () (&( (" " '( &)$" &"' $ (' %) ,$& ( ) ""& ( '"1 " ) ("" & "" &(&(' &)(" " $'( ("' +&(&'1 " &(&"'' )- + .4 &"1 ("+ " '( & ( '(" ( %) & " ." $& (&")& "$"' (&( (" ""& &# " "&" " ( '"1 '$ ( ' " ' "$!) #'("$&'"4 )&" " &(&" ) "' )("&'1 " '&"' %) (&( (" " "$"' ""&&# " "'( " (""'"''"' %)$ ($) &' 1 " '#" $& +& ""&1 ' " ( $& "&& ') $ ) " 1 &'$'"(&"'(&( ("' "",'() &'") (" $&# ("' +&'"' " )'" "(&"' &"'1 "" '" (&( ("" 5' $ (')&"'"'4 '( ' (" ' $"&( ( &"&& %) 6 (&( (" " "$"' " ' &&+&'7 "" $"& $ '&'1 ' " %)1 ( $&# ("' ') &"' " '"' " ' &+)& ( $ (1 ') '(&# $) ')'$ &') %)&'"&$)( 4 &'(&') +"&# ($ (1'&(&'(' ""&3 ( '1 )&# 1 - $("" " "( (4 " &'$(" &"1 +"&&'')'&(&'('&" ('1"& '(&# 1')("& -')&4 ) %) # "$" ' *( ) ' '()" ' '& +"&"& +)1" '&"'+''') ('&" " '3 89 ! "4 • • • • ) "& $+ ! &"&!!/ ! ! $ 0, " ! + " "" ) ) " ! ! ! * "" ! $ "! ! ) " ! $ ! " !12 , ! ) "+ ) ! "" ! - )% , ! + ! " ! μ, ! + ! " $ ! ) "" ! " "!' ) $ ) $ $ , . $ ! ! ! ! ! ) "" "" #!$!, ! " $ " ! "! $ ! + $ " ! ) ! ) ! ! !, & " ! "! & ! " # ' ) ! & ! " " , ! ! 3"! ""! , ! "! ! ! ! ! ! + • • • $ " $ ) ! ! !$& " ! ! " , & " " ! $ & ! . $ "& $ ! ! ! ! ! "!' ! "& ! ! ! & ! " !!) $ ! ! ! ! & "! !$ , $! ' "" " ! &$ " "! !$ /%0, " ! ! ! ) " " " " ! &! "! ! ! !, & " ! '! ! ! $ " ) % ! " " !" !!!, 13 #$"" %6 ( "$"$$ #""#%"!% # "##$$$""$'#"%$ $!%" $"#%##!% "# $"- "####$%# "" $ # # # %# $'#, " !% # #" % '% $%%)%##$# $# " "#%""%$""$'#%$ % "%"$#'"##- "# $#""%# ###$"## %##,##"$&##$# $#- ## "#"# "$",$#"%!% $%,) ##$## # "%""$#"#) , "'%"% ##$""# "$" 4-"$" "$,# # """ $#- #,#'%"%$"$#%"# "$%" "# ##"%%$$"# "-%!%#, "# "# "$" "#$ % " " $" ", " !% # #$#.μ " % "#" )" " ) " # $# !% # #$#,$"#!%##$#"$ "#""# "$"-#, "#% "##$#μ "#$" "#%$ " $"μ4,) !%, " , $*, "#%$ #$ #$' μ, " %) "# "%#%$*##"#- "#" "# "$" '" #$#$ ##, ' . #$"/#( "'-'-) "'", %"$"#"0)' # ,!% #%$-##$" %$# " # # #%" "% "# "$" ) % " "%" "# """%"-",##$# %$"%#"%'%$" "# ",#%$"$$""$,%"32!%# 1' "# "$"1- "$ , ## !% $$# # "% % "##"%"# "$"- % "",#$ ", "' "#"# "$", "#%%"'##. $## !%##$# %"#-# "#"# "$"% " #, # $#$#, (, "'"$ #$ $- ", # # "#$ "# "# "$" % "", ( "#%$ %) $', ##""%"""$#" $#- 35 "#!! $7 " ! ! #$ " ! !$!"+#"(!"($#!""#!"("$!. '"# ! #!" !""+ $ !# $ ! " "&!( $!$"$! $"#!"-#!+ "("23. ! " $ "$ $ # "#! !#.$!"$(&!(!!#""""##".! #! # " # "! ! $ ! ! !" !"!#!(".!#!!(!#"$"#!#!! "# $! $!!!###!##"##. " $#" "" $ "#! !" $# ! #!"""#&".#!"#""""" "$#!"$##!##!! $!!$$#"" " !$# # . $!"" "#$" " $ " "" """#)"#$!#!"!"#. ""!"#!$ $" $ !" !$!. " $ " !#!) ! ! $ "! "##!"#!!$"%##!##+$!$!##"" "#!$!#"#. ""!"$!$#!+!!&)"$! , " "! ! ( " " "$! (1 "$!! "#! + "! "# $ !&!" # !# !$ ""$!"#".!#"""#$ "!($&#"$(%#"!#!#!"$!"". ""%$""""!"!"#! #!!$#!####!!"$"#"" !##%" $! $"#!$#. " " $ " !#!) ! %" $ $"& !+ $ " ! !$! #" " $" #" &!. #!"!!! $"-/ "#" $(&"#"+!"$##!#!$!"&&( $!+!#!)!#!"!##(#!"!"$"#" $"! $($"!#!!!#$!+!'! " #" " $" ( $" &" ! "$!! "!# "$ $". #!$"#!!"#0. "# $ "! $( !)!+ '"# !" $#" #! " #" ( " #" " $ " !"! " !"#&!!.$!"#&'"#$!# 56 #$"" %4 "&#!%"/#$%# $# "$$#""$# !% %#"#"####*!%# "#""1# !%# #%1 $# "%#!%#$" #$"$$" " "%+ " 1 # $# # # #%" !% "# # $#!%" #"$%##$$/%!% %)#$"#%"% #"##(1""##%#"!%" % #%$ $% $# # $# $"$#/ #" $ !%# "# %$##!%$#$" "(/$" "$$ "#"( "$#1 #$ # #$%# " $" "( * # "$"#$# # "$$# ""$# * $"" (" "$( $"# # # " #$(""" 1 # # $# ## !% # # #%#$# #/ # #$"$"#$ #$##$$#$#1# ""#/!%*# $'/%$($""!% "#$# #"#%$ "% $ * #" #$"$#$ * !% ($$ # #$"$0 # #"( # %$ "# # (# "# "$ #$" * "% % "$ %""1 #$# $# # #%"#%(*#$%#" $"# #μ* ) $"1#/# # "%%"%##"##$"#/ "% $ "$ " %$ #" #$#$$/ * ( $#$ # #"#"#* "$#1#$##$(#$## ##$"$ " #/!%$%*%"" $ #$%# $"#1 #$ $ #$"$ # # " # # #$#2$#$# )$#/ # "$$ % # $+1 #$"$#%$("#!%*!%# ""/* "$$ "("1 # #$$##"##$"(#%" "%"" $# "(#$$$"$"(#1 # $# "(#%"# %# " # # # #/ * !% $"($"#"(##/(#%"#*"#/##$##%$# "# "# "$"1 #$ #$/ # ($ %" #$ #%"/ % "(#%" # $ " # "#1 #$ # % "$"#$ %* "$$ # #/ %!% # #"$ " (#$/ $$ "$" (#/ !% " #" #% "$ "#" # # #" $" (#$" %"/ "#%$ % #"$ ""#$1 34 +,*#&#&* '-#&D % # ++,$ %-*&%&*%& #&+ &(&+ $&% # +*'% (&+* (&* ,-* ,%,& +&* (&,#$& &$& +&* # ('++5 +,$-#% # +*'% 4 +&$,&+,,%4(*&#,%41&*$&%%,-*,+5%%#+*'%4 17 &* .#,$&4 + &+*/& )- # $%+,*'% *'% &(&+ (*&/& (*+'% # ++,$ %$-% (&* %'% # ,/ (*&#*,/ #+ #-#+ (*&%,&*+5 #,*&%+ % # *%'% #%&,*4 )- /&*% # *%'% #%&,&+ $&+ % # -%&%# $*'&+4 % #&+ -#+ + *- +- ,/4 )-$&,0+1,/&,4-$%,%&#+-+(,##+%&%+41$&+ %#-#+ 1#%&,&+14*-%&#((*&-*%,-*(&+7+$+$&4+ &+*/&)-#$%+,*'%$&*%%-#,*&#2&1#,$&7 - + */% # %+, +-+,%+ &(+ +&%6 (&,*$ &*% (&,#$&4$&++4(*,&%&*%%,*#4/+&#,'%-,%7 $&*% + +&* % (&* / &*# (*&4 & +- #,& *& 0,*'% (, :>4D;4 ,% -% &+(&%# $+ % ! :?B CAH; 1 $-1 /*# -% (*+&% &,*4 #& )- &# %/-#2* # &++7 *+ +- $%+,*'%4 + +,*-1 *($%, % # &*%+$&4 /*%& +- /&#-$% +,*-'% %,* ?4B A4D 8"7 #*&* # @CH $&*% +, -% (*&,%+4 -%$%,#$%, #.$%7 ,,%&%%,*&%+#/+$&*%%+,%,&+,!&+4(*%(#$%,(,&1 *%#4 (*& # (+& # ++,$ %*/&+& %,*# + ++& 1 )- + -%& #&+ &(&+ $+ *&#&+4 #%2%&+ !+ &%%,*&%+ % #)-& #&**)-& :;4 ,%,& $&*%:?D4BH#+(#+$,+;&$&+-$,&#,&,/&$&*%9C9#--*'%&:C5 ?BH#+(#+$,+;5+,+&%%,*&%+4+%$*&4+&%+-%,+(*(*&-*# ,&%#+&7 ?E %&$ $ !' @ %"& % " $&& $ & $/ && '&&&) '&&)&/%%'& % 2+ $"$&$ %&$ 5A9D6% & , 0 "$"& " $ ''$ ! #' $ % "'%& %<+?/ $$ " $4%&! $ % $ $2 % ''$! % $% + $&$ %"% %"&%#'$ $/+ " %&)$ !1?" %&)%'% + $" & #' $/" $ #'" %& &$'+& % $2 & & + $&$ + %& &) / </ " $ %$ ", & ,$ ' % & % ?/ ' %/ '#' % ' %"& %'& / !& "$ '! & & % % + $ ' % " ) $0 ' & & %/ "'%/ '$ % " $ ) $ + "$&$/ #' " $ "$ ' % % &$ % "%&% 7 $3& & %7 $&%/ "$ &) $ ! % ''$! % + %' + $ "$ '!" $) $2 %'$ &/ $& /" $&& & ? %"$ '" $ $/" $%$% %%" &% $&$%)% $5 %%(+(&"%6+"$&$2%&' % %%(%% %& '" & $3"$&$:1?/&$%#' %%(&"% $ $/" &%%) $/&$:1;+:1<2+ $"$ '! ? %%$"&%" $%$'%+ $" & $ $&$% %% (&"%2 $& "%& $%$,'&&" $& % "& +%'+)$/&$@+;932*$! %& & %+ $ %$," $)$/$ % $ $ $/?+<=/</:</@ >?/?D %%%&$/$%"&)&2%)!%'+)$/ ') $ < $%"$ $+ + $"$ %& & %5;/>@62 &$$ #' '$$ %' "&/ #' $% %$)!" '! % %$) %" $&&% $ & $/"$%%'$) $''! % & & % % &$ "$&& $2 %% / % ) '$ ''! & & ? "$! & % &!* % #' % "$ ' "$%%'$2 % % *&$% ) % "$ ' % " $&&% $ & $2 % % $$%" '%% ) '%&$'!+$& "%& 2 %'$#'$&$% '&"&$ %%+$'%&$!2 $ &$ / $ & & % '+ $& $ ' 2 $ %%&% %% " $&&% #'/'& + $%'%"&%& $'" % & % &!* %/ #' %&$! $ $ % $%'&%"$ &/"$ " $% $#'"$%$%%$%'&%$ 2 %) ! % ' + $ #' '& / &$ @ + := / '! :A %&$ $ !' A "$ &% % %! ;:F. $& "%& % $ %' '$+$*&!1$'!& % $%%$ $ % "$&$ . ' % % '% $ % " $ $ % $1 %* $%' $%"$&&" $ #' & &$!'.%"$#' %%%'%&"% 1 "%$ #' % $! &$& %&$ &%& % '. * % & #' %" " $%&(%*($" $! "$$ "% 1 $ ( $ * #' %&'$ &$% &" % $' % %"1 $ $! %" + &$! ) "%& &$ ;.? < 5 %&$!11 $ $! $&$ * $! &$ & ' % $! % "$ . &$ +$% % &$ % "%&% )% &$ = * =.? &$% %&$!1 %( ! "$&& "$$ % %$ $ $! %". $ % ' &$( %&$! B5;< "$ $! $&$ * ;< "$ $! &$ 1$& &$!"%&&$%' %%%'*($"$ %$"$% $' %."$ )&=.? 4" $%&$1 )%&%' $$!'&$&.'*% &$ %)%"% %+"$ )&%@."$ '$&C% &$ %% %'"$ $% A?F%)% $ ( &$'%'$ * %''& % &$ % "%&% )% % +&$ %=:5@:%&$!.*'$!& %>@1$ &$&& % $ '$! % $ '%! %''& " $ %' * 1 $% %&$! " $ ( &$( %. & % ) % %'$"&"$ '$! & % $&6<5=7." $ #'%%"$% & & '&+$%%%&'%! &' % &$ " $ "&1 * $ % %%&% "$& $ '%! &' %&$!$"2 %31 $ ( %" & % '* %&&0 % + &% &$ % #' % & '$& ($% $% 6%& <> 7 %% " % ' $ #' "$$ % &" %" $#' / % $ . "% & $'! $ &$ % %'&% "$ "$ '$ & % %%5 & %1 % " %$"$%&&( .%'" %!%$% $ %($ .$ % '&%'%&$!" $'#'$('#'.'$! & . % $ & &$% %&$! &$( %. % $(1 )%& $% "$ %&$! $ $! % %& #'. '#' $#'$ '% &$% $% "$ +$ %' ) &$!. & & % '$& B5;< $%1 '#' $%'&&" $("&.%'"& % %$( %& "$ % &! " $ #' %'% "$ "% % $ <: #$"" %? #$'. # "- $ %$ !% # $$# # ("$# " ' "-#%"#%%#$#!%#"%%$ $#'"##/ $"'##"""$#%$""# " % $"' <3> / " " "$" * #% ( $#;<"#)#$#$@9:"#/"'/'/#%$#* #%$#- "#%%"##:;"#/"'#%%$# '$"$'%# $'#)# $#$%$"/"# "#$ # 9C ) :C 98 ) :8 "# $'$- "# " $98):8-) "#) #%#""$"=-98-9=-;8->8- 988):88 "$ " #%)- #% - %$ $ #"#)"#$(/ )" # # &$ " 0 *" ## # # ) %$"$$1 %#$!%"$"# ;3<'#)"$#/ #%$# % $'- $- ) " "#- "%$"#- ) % #$"- %*"####"$""##"# %$# '# 48/=39 22:<"#5 % #$"$ #% "'# / #$ ## "%"#:/=3=2<"#") $##$"-) :/= #2< "# # (#$ #% " ""##/ % '""# %$" $$"'##/ ""-*"# " "#'"$/### %$"%:=C# $"""'-%=8C##"-)%988C## #'"/##$%"$"""#%-!%##%%$% =83988C &$ ## $# #$"# - "- % " " " "$"/ ## #- $2 #" !% % #%"# % # $ #$ *" % $" ## 4 " $ :3 ; #- #$;3<## $#"!%%$'$-%)### "#5/ '* #% $" "- # #" " "# " "$" 9: "# 4# #% ## " ) # ' $" #5- %# $ % $/ &$ ## " " " $ " ""###"$4*9"5/"## "#$ " " $ 4;8C ## " " " ##$5- ## #/ '" $- "#%#$"-%!%" # '# # # #$" % # "$"# #/ ' " # "" "%#%$"##"" " ""$"$'/"% #%%$ # # $ &$ " #% # % #" " 4* # 9839=+5/ ' $"'# # "#"' " ## %#- "#$ '$ % )" $( "%" " # # #$# 4* :9 #$"" %6 # 5*0- & "$ # % $"$& "$" % '#$ "# %-#$$# " "#"##$"# "'$ )+%&$ "" #+(!% "$#% """ &# # $ ##$ "$- &$ #% #" ""$+ # "#!%"$#$ -%#"$#$#+%""5.21 % $ #$ % "%- # $# %" $"$ # %#"$"#$# $($ "+%$ "!%" "$"" "%$##%"#$"$#- #"#+#%" $#+# $#+(#"$# %#%"#$##$# "#"#"($"# #+"$ #%#$#&"##- %#$!%"&"""$%"$+ %"%" #%"$#- %"#$!%"$"$"#$" &#+ % "" "$ %"" # $ # "#$$#, #$ $ # "&"$ "'- '$+ "')+ # $ "#&# $"# ( # $#$# % "$" $& # "+ " $# # "%#$# "#"%"%( +#$"$"&#$ "% % # %( " " #% $ # " $ %( " $ /41 "'$0,#$"" $+&"%%"$# !% "#%#&( "$$#%$-$%$## %&# &# #$" # # ( # " "++ !% "$ %(" "#%$(&"#%%#$"$$# "#- 33 ! "8 ! # ! " " " "" ! ) & # !"! ! 23,27 ) " ! "! 59,83 * ! ! "% !! - " # 27,33 . " ! ) ! ! 36) 61 % 211=*,2) ! ! ) " !! ! !# ) " !!! !# * $ ! ! !! - . !# " ) ! 311)511)911)2*311%2*711 " " !* " !& " " "# ! " " ! !! !# " * 36< !! ! ! "& " " % ! ! "* 86< !! ! !! !-! .) !86<2+4!" ! !! !%61< !!!! ! % * ! % * & " !" ! *"#! ! *! %"# !!" "! * 34 !" #7 # + !" "%" !"+ "# !('#+'!!!" % +!#!" ! ! ! !% , ! " ! !, ! 23-28 ! !# # ! #" ""'&!"#"!!!, '# # !!%+" "# "41!+ ! ! ' # # " #" !# , " &" 23 ! ! "% ' # " !# 4 5 ! !" ( %! !"!+ # " ! ! % # " 35 !, ! #"! !! ! 36 73 !, ! ! !! !"! !##"" " " ! !!! 311 !#!"!!! %# !"!# !# !73 !+ "!# %" ""! "" ' ! ! ! %! ! ! !"! #"! . " !# " ' (+(!% "! " "! %" ! . / ! " # ! " $"!! ""!!" !+! !! % ! ' ! #" !" +#31;!!! !" """ !#!, ! 73 ! ' # # " ! # #% # !! !# 36<,-2'!"# !", 35 '(&""& #)"> ('%) " ("""$"'"'' '&9:3=5:<43 ( "(& '&""'(&"'&( (+""""& '))( ( " ) (' '& ("' ') &"' 6%).' "' '(&! (" - '" " )& 1 ) %) ' (&'("& "' ')!" "()& "'71 "'(& " ) , ( )$ ("$"&$&("'$ ('3&' (+ (')#"$&'&$# - '"$&""$"&$&(&( ("""&&# "3 (""&& " (&"&'" "& -) +." ')"$'&"''%) ' ( "3 ) "&$&$&" (&"""& )&"$("%)"(&"'"$"'3 "' $ (' " &' '))( $) " '& ("' '( '(&($)'# "''"&) (3 '" (&" ''&'$) ) (&94;" &""&,(& "1"%) ,) )'("''3 "' ("' +&'"' ( " (& '&" $& '& '&' &'(" "$"'1 ) %) $& ,'(& ) ' + (' 3 & ' ("&" $ (' %) & "$"' "& &# 3 $"+ (# &'$&("& ' 6:A73 ' )'' '" &) (' $&" (& '("&' 6:;A7 "& 3 ) 98A "' '"'$&"'1'( 1')"&# -'" " 3 <A"'$ ('$&' ( &" ' (#$' )( '3 "& '(&! (" ' ) & + ( $& "'$ ('3'( ;=A"''"' )'"' )'", ('""$&",'3 '# '(& '("&-&"$."'"$&)) ' )# '" " " &'$(""& "&3'('&) '( '" (&)- +$ (3 '&("* '"&)3 ( ) "' &'$&("&"' - ' ", " ')$ (&") (" & (""''3'( "$&(&( (" &'' ""& &&)$(+" $ (' " "$'' %) '( & " "" (&( (" "$"'3 ')(." !"'""'# - ' $&"'"'""&"'"'3 ' ) &" " # " '(5$&1 ' ) "&$+ " " ( ( &+ ( 1 - '"& &$("& 593" $"( :85;8 +' " &'$(" "& 3 &( ( (" ') $" ""& &# " "&)# $& $&1 ) %) ,'( "&' (&# 2 "& "$&"'1 ') )1$& (&6 (&)')&1 (&+ "' (73 := ! "8 ! " $ "" "" "! !$ ! $ ) " " " ! " !" !7,9 " ! ! 1)5+9 * "! ! ! ! $ ! "! " !! * " ! $ * !" " " ! & ! $ " ! " ! ! ! ! -:7=.) ! & , "" -" .% ! ! """ * ! ! % " ! " $ " * ! " " ! $ ! % ! * ! " ! % ! # 46>+81>+) ! ! ! " 2 -46>+. -81>+. & ! ! ! )211μ+) ! " !!! ! !* 4 ! " ! !% * 37 $%## &= !!#'$&&$$8661:66<1>#$.&!## # %#$#$#!####' )# $'#%#$#-$!%$"&#$!$$ !$. BUPRENORFINA TTs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μ ,. &'%('(%$(!+!!49<%!+3?0@%!+!!5% ! ! &! $( !+!%! % !%1 !( !+!!0 !#%"!!%0%(#!#!&";&%#-!#!%(%(#! ;0,%(#!#!&">&%#-!#!%(!+!1,(&# (%(!'%?,@0,+&'(%(#!!9<1 #&%%&!#(%'(!&@8 !&0&#%!#&%!"& &&,'!+!!!+!!&!&&'&'(&1 (&!"&&!!!'%!&!#!&,!%&1 !#%" ! !%0 !+!! #!& ( !&#! ,!% #!% * !%#%!+''%(>8D,(@?D1 ! %%' &( '!-"0 ( % #%!#!%" !+!! &(% ( 3 $("!%!+!!(%'#%%#&!,#%!+'@39<D!&& & +%' !! !+!! % & :< &'%"1 &(% ( 3 '" !+!%!0 $( #!& #%!#& && , #!% !'%(% '! &! !+!!1 %!0 %'' & !&'%! $( !& *& !+!%!%#&'%&&'%"!+!!&!&#%&0,!% & !'%! #%#' !% !(1 ( &'(! & !'%!& #&'&!+!!(%!#%!+':8*&&(#%!%&&!+!%!0, ,!%'!&!&!#!&&!%%!%!&!!&*&#&'!& !+!! $( ! !& !+!%!1 !%!+!!0 #!% !'%%!0 % '! &!1#!'&'!'!((%"!!+!!!&*(!1 '%!%!!&%#'!%&0#!%%#'!%(&'%929892<8 !%,<*&#%1 +!!(&*"!&*&&%!&#%!'0'#!'!!) !&!&'&!#!&1&!#%!!(&%"&'1 &"&!&#!&!'%!!#'!!!%!%!3&*%!1 #!' '!#'* !+!! # * &'%"1 !+!! &'% &((' '%#%'! & '% : , < *& & #!'' $( !% &!% ( & !(%1 %!0 !% & 9< *& & - $( :A !7 $ +% !! 3*2 *$+ $# !!!21$ ! 211+ $ 3,4 % 4,5 %21#) !!+ $# ! & +% 2! + #!$ ! # *! 1)6#)%! ! # 7 ) ! % $+ + #! %+ ! ! % # % !) +)!$ ! # + ! %# ! ) ! ! +! ! ! ! & $ + )! !! ! $+ !! ! !$ + !!$ !+ # $ # + 31-51,23! + ! $ !) ! % !!! . % ! /+ ! ! ! # ! ! $ ")% !! !! ! !!+ ! $ ! ! + ! ! !! . 2+411 / + ! # 41 !" #: !##" !# (! # " &"!* * (" *" " ! !- !! %" ! !" !%!" ! ! !##! %!##!# !#- ! " !# #! % " " # ' # ! ! %!!!"!""%!!"#!!- *!# # !!! #! # #! ' " ! !"! !- ! !! #""! & ' !# !" *#"! 4,4- !# " ! !" # ! " ! !"! &!!%!/" 73'<3?0'#! 5- " *!"!"!!" !& # !* #!*##"!& !!!- ! " """!!"! !!"% - ! !# & ! " ! ! + ! ! # # % 4 % "! " # - " !"* ! ! " ! # %!## !- !#&*!# "#!# 4,4*!#!!" !*/@0'/.0" -!#!"#! " !μ' " ! ' - " " ! " ' ! " ! %!! !"!- # ! # !! $ ! 9;?* !! "! % #"!"<3.433?*#&!#' " "! !# ! (* # ! !#""!" #"!!-;3?!"( - & " % #<3?*!!%8 !- 64 &'%!!% "(!? &')!!!!!'%#!&!!#%'!!&!!%!%! ! !%!3&)%!1 ( #%& !! +()' !& & ! #%'! (%' %&&!!%!&&1 ! !!% !%! &(! &" 1 (', !&& =83 988 > !%& #!% ) !%0 ! !&& * <88 1 ! % ! ! &( % 4 " & & ' &' &!5 & %! !,% ! !&&&&4?=398825+2!#%!!%'%)!'%!&&@!%&4(% '( > !%&51 ( '! !, 983:8 ('!&1 + !%(!& %" %'% 98839=83:88 #% &( &'%" 9: !%&1 & #!& &' !%,& )& 9881 ! #!& &( (&! #!% ) &(('1 !% ) '%)!&#%(&"0&#((%(#!988988&(%!&!"! #&%:8('!& !& '!& )%&!& & !(& &! &!!0 #!'&"0 '$(%0 %!&0 !(&" '0 &$( !0 &!0 (&&0 )"'!&0 + &'% '!1 &%&&##'&&!%%&0&#%!&&&(#%!%&&%!&!#'& !&'!%##&1%&'(+!#!'(&!+"0+#%!& ("%&#%'!%$(!'%!&!#!&1 #!!%&!'!%+#1 ;: ./-%)%)- *0%)I )'.'/ & '/)+/)%%!' %)%)-%-/&)0/> /)$ %'/- )@A< )'=)(???????????????????????????????????)''6?????????????'/ '4+/.0 - %. ' )'. % ' % )%)- .)- % 0.) &)- ' ) .0. - 2). +- % /-/& '/) % )%)- -*' ) ') &% ')< '/ ' ,0 .0 & ) ') ./ )% ) -/-% ). & &'/).: .! )&) ,0 3 ./' )/-). +). %. /-/& '/). 4 ,0 . % ' 3+% ) %). - .). 4 ' ). %). & .&).< ; +/,0./& *')'%%2- .).+)/' %.:. ')%).&.. ' / 2).%).. 0 '/.; C<>+'' !. ;+- *'0'.!'-)&./ '' @'-2 ). .&):+ %%% ':.0)- *': )%)-.&0.0%-.:'0..2*& /).<<<A/-.% '/--0+ *'.1 /%/-/& '/))-0 *' &+)-/'/ %). .< D<>+'' +.!,0 ) *';.0''*&')+.!,0 )-/- 5)+)-1.,0)&+0%. 2 %& *'40'.)+-)0 -/).+.!,0 ). '+' '/&'/%% 2 )%)%)-< E<>)-). *'; .)-). .)+ ).+0---+--.+ -/)- 4%&0-/< F<>& ). &'/%.; )&) +0' .- )'0. *': . *' ) & ). ' % % +- +'.-< /).,03 '0' -/+-0' '%0.))&'#)2!0%).&)/)-)&,0 '- +% -).< /-). /). .0'- ). +0' 3 ./ -: +-) ') .)' % & /'/.: /%. )&); '0..: ./-( & '/): .& '0 *'%+/ /):+-)%&.0- '- ).:+-. *'4 0%/..30%.@ &+)/' 4 .& '0 *' %% )A< C<> +/ ,0 % & *' )+ ) .)%) .- +-.- / . .0 & ) )'. - ,0 ./ /-/& '/) &#)--!%)%)-:%+-/ + *''%/-#)4%.-% )'..) %.< D<> %- ') /'- +-)%&. 0.) -). ) %))%: .! )&) ') ./- '2)%0-) ' % 0.): 2'/:+).. *')/-'.+)-/.0./' %%. E<> )&+-)&/ ,0 %). )+ ) . ,0 . % +-.- ' .' +- 0.) 3%0. 2) +-)+ ): ') +-& / '))/-.+-.)'./)&- & *':.!)&)')/)&-&.& *',0%,0.% ' :' %& *'+-.- /+-)/-+-.)'< F<>+/%()+)/' %,0%).)+ ) .+00.-%' ():'%.0+0./),0-&-5: ')')/ - '& /&'/./ -0'./' %' %)%)-< G<> - % & *' .)%) /-2. % ' % )%)- ) /-2. & & ) /' *' - &- 42 .-'/ +&'/%.'. .,0-,0 -'& ).). .@ -0!:3/- )'. '/%.<<<A H<>+/,0%.-/ -%& *':. #0 ).0& ):')3 ./'' ).&)./-%. '.0,0- - ):)+-0' *':)..--)%%'/)..0'- ).:. ',0+)-.0+-/. 3 # -.+)'. % %0' %). & ). % ' % )%)- +)- %). +-)%&. 0.). +)- % '/--0+ *'%/-/& '/))+ ) < .-'-/).%).& &'/).)+ ) ..)%). ./0-))'/)../.)' )'.< +/ ,0 0%,0 - 2 )% *' ./ )'/-/) .0+)' % '% 5 *' % /-/& '/) )' )+ ) .< +/.!& .&),0#0 )%!' )%).& ).%' %)%)-%/-/& '/))')+ ) .+0 .- '/--0&+ )'0%,0 -&)&'/)< !)./)0&'/):'/ '.0)'/' )40'25+-0'/./).%.0.:.0&%).- .).4 )' )'../)'/-/):%0%.%'/-0')+ < -&%+ '/??????????????????????????????????????????????????? ??????????? EE 231*.*.1 /4*.N • • • • • • • • • • • • • • • • •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