Farmacología de los analgésicos opiáceos

Anuncio
#$""
%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"%*,"**,$$%$#$%)!$!"%*)'+%)*
μ . #*3 * ')%',*+% " /!*+$! *,+!'%* )'+%) ,)% %$
*+,!%*)#%"&!%*0%#'%)+#!$+%5")'+%)1,*+!.%*"+!.#$+'%)
0"%(,%'%)"$+%$!*+40")'+%)2*+!.%*"+!.#$+'%)"
"+%)!$
0"%(,%'%)"$+%$!*+5%#%*!)+#!$(,#%**,+!'%*
*%$+!.%*'%)"*$"!$*0'%)" $%)!$30"%(,%*%$"+!$!'%)"
$+%$!*+$"+)!$%"5
")'+%)%'!%!/ !,$"+!$!'%)"%*%$!*+*@;3?CC0AD3@D>0
'%) " $+%$!*+ $%)6
5 *+,!%* )#%"&!%* *,!)$ " '%*!" /!*+$! +)*
*,+!'%*)'+%)*. $!$+$+%$%$+))%#',*+%**"+!.%*(,')#!+$
!$!)"/!*+$!*,+!'%*)#%"&!%*')*+)'+%)3)+)!1$%*AD3@D>
%#%%$!*+<3CD3ADA(,*%#'%)+%#%%$!*+2 ')%%#%$+%$!*+<30
)#1%!$ 0 +!"+%!"1%!$ 78 %#% %$!*+* 2 .%) -"+!#%3 * *)!+% "
"%#%%$!*+3.
@
)*( $ $(
%+ $B
$( )+ &(*4 (&*$( μ &()"* +" * " &$( $")* &&*$
4 !$(" / )+ !*$ *$ *-$ !$("6A ++(%"$4 ) $!$ &$( $)
"*$")*)/" $.$""5
!$("4)"!($4))+" $)(&*$() /,
+"'+$""5)*+$)(!$ %$)*!")+(" .)*")+*&$)
(&*$() μ : μ</μ=4)"$)*, *!$ '+&()()&$&( !$("5 "*$")*" $.$"0")!& &( "%" $)(&*$()μ "μ</μ=4 )( )+*&$μ1)") " $.$"0"4!"*()'+ )+*&$μ=)")") 5
$) &(!($) "*"*$) &( (*(0( !$ + (!"* $) (&*$() $&$)
+($" "(+*+$)$)5 &+(%" &($*" $ &($*") ) '+ ) +"" $)
$!&+)*$)$&$))-!&&$( !& $)+)*"))"*+( 0"*)&()+
)$ + 0%" '+ '+ &(( & +"%" "$) )&$)5 " +"
)+" &($.!%"4 ) +* 0($" "$) !($) (*-!"* '+ ) +""
$- "*!"* (&*$( / &(!*" +" !$( )+!"*$ &($)$ &+(%"4
!) +)$*("*)!)+(*)" &($)$.*(%"/&+(%"5$($*(
&(*4 "*(&*$()&()"*)" $)*$))*+$)(&'+#"( %"
$"$*($)$!&$""*)&()"*)" ) + )4 $'+(&()"*+"&($ !$" 5
," )4 ) $(($" &+(( &( !"* / ($")*(+( " !$ $) !!(" *&$
-)+ +") &($*") $" & +"%" "$) $&$)4 +"'+ &()"*"
(")(")4>@D?4"+"*$&)$!$ + (5&(*()*)&($*"))
($""*"*$))+"(+"&$ &&*$'+&(!*($*"(+"$ $"+ %*$&(
)(+* 0$$!$)$"")(+*"$)"$*)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, *%& " % &'$&$&& '$ " #'&! %&% $ &$ &" $"& $%1
$ " "$ & &" %&$'" % $1'" &&& % '& %%"$ &"$!& %)$% %2%&$& /$&!
'$$/ "$%! $%"$& $/ &13/ % %& $'&& & $ #' & %'
'&,!1$ %&'" &&% /"$ %'$!&!
#' + $ "$& % "%% % + '& $, %' '% %& !1 54
%&$ $
!' :
"&%65)% %" &&#' $+/%'! " /+#'$%'%
"$ "% & $%/ $ &!*% + &$ % & % )$% % 3$) %% / & $
'%'$/ )'% %/ % $&! ' %4/ "$ & $ % %'
& & $"&/#'&*&$ $$&%''&,!2& %95695
)%%" &&#' $2'$" % '&%'% +$",
%' !0 #' % "$ ', %% $ & * % &$ & $ #'
*"" '% #'%&$ %&'&/&& %&% &$&& $2%$&&/%&$ ' &$"'&%'& #'
%7)%%" % '#'&$ $+ '" &%65)%+ $2
& %$&%" &&#' $"$ +''"$% &$
%'!%+& "$% $$%"$!/& $#'%&$!
%% $"&%/ "$ ' ''! $ &% "$%! $%"$& $2 &$&& $! %) ! % "$ / ! & % & %/ % " % '&$ &$) &$ %%2 & / *&$ "$ " * / " % $ ! % + & * )
3$/"$%!$%"$& $/ )'% %+' %4%#'&&$)
%'& & $"$ " * /" $ #'%''% %'+$' 2&$ "$%&'
$ % $ $"& $% μ + ( $/ % $ + " $ #' %' !
% % $ + & && & , " $ * / #' "$ &
%&$ #'"$&" &$ %% % &)!
%%&%%$ & $ %+ $$$ %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>#$.&!##
# %#$#$#!####' )#
$'#%#$#-$!%$"&#$!$$
!$.
BUPRENORFINA TTs
$ !#$ $ 9;- ;8/; ) =6 @.17 ) $ ! =8 #$. %* $$%
%#.&"&'$6/>-7/8)7/<0#$!%'%.$%#
## #1$'# ) .
!# $ ) &%*#- ) ) "& !#&## "& % $&!#
&$ $ #$ $% %% !. #$% $ !&
&%*#'$&&-#*!#$6/8-6/:-8)>-!#$!$
% #% # #$% % %#$&$- $ #!.
$ %$ #'$&#$. $ $%&$ #*$ )# $ %$
'#$$ $ '$ ) %#$%#$- $# % $ ) #- ) $ #$ $
&#%$&)#'$#$)%#$%#$.&!##($%&
#$ !#$ #$!#%# &) ) "& ($% % % !# !#$ #$!#%#. #%$ $$ $&!##$ 6-76 0 $ $#' !#$ #$!#%#-
&"& % ( ## %# # ) &# %- $$&!##27603-##"&#2$$6-961963.&$
% $ $%# $% % % !# !#$ #$!#%# 2$- % .-
7??:3.!#&!#=8.
8=
()'##'
$*#C
!%!)(&*!#!)# #%', !))') !)##!#%#((#!'
%'#!#!!)'$! (%&*"2#((=C5A#?A 65
!%!)(&*)# #%', !)#%#( #()!'!*!)')
#!,'($!2)',(#(( 5
#(!('#*()#((!%!)(!!#(#!!(*!'!5
*%'!#'!!#)!)#)#%'!(!* !#(5
()#!)'!!%!)(#!%'(!(#!#%'!%#),##
*&*'(*(-%!)(2#!%!!#%#(#!)') !)#%'()!!
#%#(5 )'#!( ! ( &* ( *!#!( . !)'# '(%')#'# ()! ', !)
"( # %*! ()'#5 !)( &* ()! '!# )') !)# #! ' #(
!#'( # &* #( .!)# # ! ( +) ( > ( !(5 !)( #!
()!',(2#!'* )' !(2 '/#5
# ( !()'' #! #)'#( #%#(2 !()(#(2 %!$)#(2 (!)(2
!)%'(,#(2 !*'#%)#(2 . )##( #( ' #( &* %' ! '(%'$! . (() !',#(#!)'5()#() !%##5
( !()'#!*!) !)#!!#'(?@4
!)%'(,#(4*#-)!2!#'*#-)!2*,#- !3
!)!#(#(4')'# !2 )'#!/#2!#'#-!2*#!/#2)##!/#3
!)#(%'4')#!,'2!!,'2(&*!,'3
!)#!%),#(#'(4()#!#3
!)'') #(4 #'#!3
!)*'#(#(4# %'/#2%*,'(!)!(5
( !()'#!*!) !)#!!*)#'(?@4
!)%%)#(4' %!2!#')2!)#!2%' #!3
#')#(4- )(#!3!)!#(#(4'*)!2' %!2(%*
()'( !*5
#!2 #! *! %#)! ( ' )' # 8=6B7=6=> %#)! #'!92
!* (()'" !)#.#!*($! !)2%'#( !#( )/!)5* )#/$!
#'! 8=<G9 ( !)'' %#' *#-)!2 ( !*.!# (* )#5 ! !!# '
# !/'(#!#((=A @7B#'(8#(( - >@< 695
*)/!#((?<7B< @6B#'(5'#,#,$ )#(2()'" !)#2,')#
.(# !#!5
>D
&'%!!%
"(!?
+!!&(%*!&&''!'0(!!#!&(
&0!(#@0=1(#!&!&(#%!%!%1(("#%!'&
!&'%!0&(!&'!#!#(%!!#!%!&%#'!%&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
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
*/19= @@ 1+.2 ,*#!2%.2 .0%.2@ , @ */19 C@D= 1+.*.#& 4+,@
22.,B*53@1*.,@HPPI
*/19=@1+.28.*.1@%31#.,1%@IGGK
/,B*=@5.*4%/,"%*.#,!3%*.*.1@*+,3.2@KM?HPBIJ@IGGI
.,B*= @= %**1B19= @= 149= @= ,3/,= @= #= @= .3.= @= CD@
++4,.$%23.$+%**.*%93%.,,*31.0$82%.*.#%*3%.,.",.%03%,A.10$,%,B
%,3$2,%*C*%72012D,41.,[email protected]%33@JHM?HKHBHKK@IGGH@
@%20.,%%*%.0%.201*2,2%2+!%28%,3&"%2@
6.1)@@HPPM@
.1**3$1#,%93%.,@@,10%,1*%"@.1**3$1#,%33%.,@,5@HPOM
* .*.1 , * 013% * !%. 3,%/, 1%+1%@ %1. *,. 2.1 * .*.1@
%,3234%.2.%.*/#%.2
@,.**=HPPO
41%* = 1% 1%2 @ .,31.* 1+.*/#%.@ ,? .,2%1%.,2 , 3.1,. *
13+%,3.1+.*/#%.*.*[email protected]$1+=@@PJBHKG?HPPJ
,9 13%9 @ ,*#!2%.2 .0%.%2 , * 313+%,3. * .*.1 2.%. * ,1@ 5@
,1IGGG>HKCLD?HPGBIGG
7013.1)%,#1.40."3$41.0,22.%3%.,".1**%3%[email protected]$%,%,,1
0%,?+.2."+%,%23133%.,@1%3%2$%*.41,*HPPM>JHI?OIJBOIM
.13,.8 = 8, = .*499% = 2$). = 822 = 42$ 3 *@ 1* 31,2+4.2*
",3,8* %313 CD ".1 3$ 313+,3 ." 1)3$1.4#$ 0%, %, ,1 03%,32? .,31.**.23%313%.,2348@%,HPPP>NPCIBJD?JGJBHI
7013.++%33@,10%,1*%",0**%3%[email protected]**3$1#,%93%.,@
$,%*0.131%2=OGK>HPPG?HBNJ
.4) @ 4231*%, +,#+,3 2313#%2 ".1 .1* .0%.% 42 %, ,.,B+*%#,,3 0%,@
41.0,.41,*."%,IGGH>LC400*@D?PPBHGH
-.2@45201203%52,*+0*.*.2"1+.2.0%.%2,*313+%,3.*
.*.1@5.@20@.*.1IGGJ>HG?HMOBHOG
143**@%/,*.2.0%.%2,*310!43%*.*.11/,%.@*31%.,2*
.,43 (. *.2 "3.2 *.2 .0%.%2@ 5%23 * %* +% %%, 3*4,8@HPPL>HGC240@HD?NBHI@
666@215%2*4@.+A*0,2A,431%%.,GO@$3+D@
JK
Descargar