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char = s;code = 115 char = s;code = 115 char = i;code = 105 char = v;code = 118 char = e;code = 101 char = ;code = 32 char = d;code = 100 char = e;code = 101 char = p;code = 112 char = r;code = 114 char = e;code = 101 char = s;code = 115 char = s;code = 115 char = i;code = 105 char = o;code = 111 char = n;code = 110 char = ;code = 32 char = o;code = 111 char = f;code = 102 char = ;code = 32 char = p;code = 112 char = l;code = 108 char = a;code = 97 char = t;code = 116 char = e;code = 101 char = a;code = 97 char = u;code = 117 char = ;code = 32 char = a;code = 97 char = n;code = 110 char = d;code = 100 char = ;code = 32 char = r;code = 114 char = e;code = 101 char = d;code = 100 char = u;code = 117 char = c;code = 99 char = t;code = 116 char = i;code = 105 char = o;code = 111 char = n;code = 110 char = ;code = 32 char = o;code = 111 char = f;code = 102 char = ;code = 32 char = V;code = 86 char = (;code = 40 char = m;code = 109 char = a;code = 97 char = x;code = 120 char = );code = 41 char = .;code = 46 char = ;code = 32 char = 3;code = 51 char = .;code = 46 char = ;code = 32 char = I;code = 73 char = n;code = 110 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = e;code = 101 char = ;code = 32 char = c;code = 99 char = a;code = 97 char = n;code = 110 char = i;code = 105 char = n;code = 110 char = e;code = 101 char = ;code = 32 char = c;code = 99 char = e;code = 101 char = l;code = 108 char = l;code = 108 char = s;code = 115 char = ;code = 32 char = L;code = 76 char = -;code = 45 char = t;code = 116 char = y;code = 121 char = p;code = 112 char = e;code = 101 char = ;code = 32 char = C;code = 67 char = a;code = 97 char = ;code = 32 char = c;code = 99 char = u;code = 117 char = r;code = 114 char = r;code = 114 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = ;code = 32 char = (;code = 40 char = I;code = 73 char = (;code = 40 char = C;code = 67 char = a;code = 97 char = );code = 41 char = );code = 41 char = ;code = 32 char = w;code = 119 char = a;code = 97 char = s;code = 115 char = ;code = 32 char = d;code = 100 char = e;code = 101 char = c;code = 99 char = r;code = 114 char = e;code = 101 char = a;code = 97 char = s;code = 115 char = e;code = 101 char = d;code = 100 char = ;code = 32 char = b;code = 98 char = y;code = 121 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = y;code = 121 char = m;code = 109 char = o;code = 111 char = l;code = 108 char = ;code = 32 char = i;code = 105 char = n;code = 110 char = ;code = 32 char = a;code = 97 char = ;code = 32 char = c;code = 99 char = o;code = 111 char = n;code = 110 char = c;code = 99 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = r;code = 114 char = a;code = 97 char = t;code = 116 char = i;code = 105 char = o;code = 111 char = n;code = 110 char = -;code = 45 char = d;code = 100 char = e;code = 101 char = p;code = 112 char = e;code = 101 char = n;code = 110 char = d;code = 100 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = ;code = 32 char = m;code = 109 char = a;code = 97 char = n;code = 110 char = n;code = 110 char = e;code = 101 char = r;code = 114 char = ;code = 32 char = (;code = 40 char = E;code = 69 char = C;code = 67 char = (;code = 40 char = 5;code = 53 char = 0;code = 48 char = );code = 41 char = :;code = 58 char = ;code = 32 char = 1;code = 49 char = 5;code = 53 char = 8;code = 56 char = +;code = 43 char = /;code = 47 char = -;code = 45 char = 7;code = 55 char = ;code = 32 char = m;code = 109 char = i;code = 105 char = c;code = 99 char = r;code = 114 char = o;code = 111 char = M;code = 77 char = ,;code = 44 char = ;code = 32 char = H;code = 72 char = i;code = 105 char = l;code = 108 char = l;code = 108 char = ;code = 32 char = c;code = 99 char = o;code = 111 char = e;code = 101 char = f;code = 102 char = f;code = 102 char = .;code = 46 char = :;code = 58 char = ;code = 32 char = 2;code = 50 char = .;code = 46 char = 9;code = 57 char = 6;code = 54 char = +;code = 43 char = /;code = 47 char = -;code = 45 char = 0;code = 48 char = .;code = 46 char = 4;code = 52 char = 3;code = 51 char = );code = 41 char = .;code = 46 char = ;code = 32 char = I;code = 73 char = n;code = 110 char = ;code = 32 char = a;code = 97 char = d;code = 100 char = d;code = 100 char = i;code = 105 char = t;code = 116 char = i;code = 105 char = o;code = 111 char = n;code = 110 char = ,;code = 44 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = y;code = 121 char = m;code = 109 char = o;code = 111 char = l;code = 108 char = ;code = 32 char = (;code = 40 char = 5;code = 53 char = 0;code = 48 char = ;code = 32 char = -;code = 45 char = ;code = 32 char = 2;code = 50 char = 5;code = 53 char = 0;code = 48 char = ;code = 32 char = m;code = 109 char = i;code = 105 char = c;code = 99 char = r;code = 114 char = o;code = 111 char = M;code = 77 char = );code = 41 char = ;code = 32 char = a;code = 97 char = c;code = 99 char = c;code = 99 char = e;code = 101 char = l;code = 108 char = e;code = 101 char = r;code = 114 char = a;code = 97 char = t;code = 116 char = e;code = 101 char = d;code = 100 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = e;code = 101 char = ;code = 32 char = i;code = 105 char = n;code = 110 char = a;code = 97 char = c;code = 99 char = t;code = 116 char = i;code = 105 char = v;code = 118 char = a;code = 97 char = t;code = 116 char = i;code = 105 char = o;code = 111 char = n;code = 110 char = ;code = 32 char = o;code = 111 char = f;code = 102 char = ;code = 32 char = I;code = 73 char = (;code = 40 char = C;code = 67 char = a;code = 97 char = );code = 41 char = ,;code = 44 char = ;code = 32 char = i;code = 105 char = n;code = 110 char = c;code = 99 char = r;code = 114 char = e;code = 101 char = a;code = 97 char = s;code = 115 char = e;code = 101 char = d;code = 100 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = e;code = 101 char = ;code = 32 char = t;code = 116 char = i;code = 105 char = m;code = 109 char = e;code = 101 char = 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e;code = 101 char = ;code = 32 char = s;code = 115 char = t;code = 116 char = e;code = 101 char = a;code = 97 char = d;code = 100 char = y;code = 121 char = -;code = 45 char = s;code = 115 char = t;code = 116 char = a;code = 97 char = t;code = 116 char = e;code = 101 char = ;code = 32 char = i;code = 105 char = n;code = 110 char = a;code = 97 char = c;code = 99 char = t;code = 116 char = i;code = 105 char = v;code = 118 char = a;code = 97 char = t;code = 116 char = i;code = 105 char = o;code = 111 char = n;code = 110 char = ;code = 32 char = c;code = 99 char = u;code = 117 char = r;code = 114 char = v;code = 118 char = e;code = 101 char = ;code = 32 char = o;code = 111 char = f;code = 102 char = ;code = 32 char = I;code = 73 char = (;code = 40 char = C;code = 67 char = a;code = 97 char = );code = 41 char = ;code = 32 char = l;code = 108 char = e;code = 101 char = f;code = 102 char = t;code = 116 char = w;code = 119 char = a;code = 97 char = r;code = 114 char = d;code = 100 char = s;code = 115 char = ,;code = 44 char = ;code = 32 char = b;code = 98 char = u;code = 117 char = t;code = 116 char = ;code = 32 char = v;code = 118 char = o;code = 111 char = l;code = 108 char = t;code = 116 char = a;code = 97 char = g;code = 103 char = e;code = 101 char = ;code = 32 char = d;code = 100 char = e;code = 101 char = p;code = 112 char = e;code = 101 char = n;code = 110 char = d;code = 100 char = e;code = 101 char = n;code = 110 char = c;code = 99 char = e;code = 101 char = ;code = 32 char = o;code = 111 char = f;code = 102 char = ;code = 32 char = a;code = 97 char = c;code = 99 char = t;code = 116 char = i;code = 105 char = v;code = 118 char = a;code = 97 char = t;code = 116 char = i;code = 105 char = o;code = 111 char = n;code = 110 char = ;code = 32 char = r;code = 114 char = e;code = 101 char = m;code = 109 char = a;code = 97 char = i;code = 105 char = n;code = 110 char = e;code = 101 char = d;code = 100 char = ;code = 32 char = u;code = 117 char = n;code = 110 char = a;code = 97 char = l;code = 108 char = t;code = 116 char = e;code = 101 char = r;code = 114 char = e;code = 101 char = d;code = 100 char = .;code = 46 char = ;code = 32 char = Q;code = 81 char = u;code = 117 char = a;code = 97 char = l;code = 108 char = i;code = 105 char = t;code = 116 char = a;code = 97 char = t;code = 116 char = i;code = 105 char = v;code = 118 char = e;code = 101 char = l;code = 108 char = y;code = 121 char = ;code = 32 char = s;code = 115 char = i;code = 105 char = m;code = 109 char = i;code = 105 char = l;code = 108 char = a;code = 97 char = r;code = 114 char = ;code = 32 char = r;code = 114 char = e;code = 101 char = s;code = 115 char = u;code = 117 char = l;code = 108 char = t;code = 116 char = s;code = 115 char = ;code = 32 char = w;code = 119 char = e;code = 101 char = r;code = 114 char = e;code = 101 char = ;code = 32 char = o;code = 111 char = b;code = 98 char = t;code = 116 char = a;code = 97 char = i;code = 105 char = n;code = 110 char = e;code = 101 char = d;code = 100 char = ;code = 32 char = w;code = 119 char = i;code = 105 char = t;code = 116 char = h;code = 104 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = y;code = 121 char = m;code = 109 char = o;code = 111 char = l;code = 108 char = ;code = 32 char = i;code = 105 char = n;code = 110 char = ;code = 32 char = v;code = 118 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = r;code = 114 char = i;code = 105 char = c;code = 99 char = u;code = 117 char = l;code = 108 char = a;code = 97 char = r;code = 114 char = ;code = 32 char = m;code = 109 char = y;code = 121 char = o;code = 111 char = c;code = 99 char = y;code = 121 char = t;code = 116 char = e;code = 101 char = s;code = 115 char = ;code = 32 char = i;code = 105 char = s;code = 115 char = o;code = 111 char = l;code = 108 char = a;code = 97 char = t;code = 116 char = e;code = 101 char = d;code = 100 char = ;code = 32 char = f;code = 102 char = r;code = 114 char = o;code = 111 char = m;code = 109 char = ;code = 32 char = h;code = 104 char = e;code = 101 char = a;code = 97 char = l;code = 108 char = t;code = 116 char = h;code = 104 char = y;code = 121 char = ;code = 32 char = h;code = 104 char = u;code = 117 char = m;code = 109 char = a;code = 97 char = n;code = 110 char = ;code = 32 char = h;code = 104 char = e;code = 101 char = a;code = 97 char = r;code = 114 char = t;code = 116 char = s;code = 115 char = .;code = 46 char = ;code = 32 char = 4;code = 52 char = .;code = 46 char = ;code = 32 char = <;code = 60 char = b;code = 98 char = >;code = 62 char = T;code = 84 char = H;code = 72 char = Y;code = 89 char = M;code = 77 char = O;code = 79 char = L;code = 76 char = ;code = 32 char = D;code = 68 char = I;code = 73 char = S;code = 83 char = P;code = 80 char = L;code = 76 char = A;code = 65 char = Y;code = 89 char = E;code = 69 char = D;code = 68 char = ;code = 32 char = C;code = 67 char = O;code = 79 char = N;code = 78 char = C;code = 67 char = E;code = 69 char = N;code = 78 char = T;code = 84 char = R;code = 82 char = A;code = 65 char = T;code = 84 char = I;code = 73 char = O;code = 79 char = N;code = 78 char = -;code = 45 char = D;code = 68 char = E;code = 69 char = P;code = 80 char = E;code = 69 char = N;code = 78 char = D;code = 68 char = E;code = 69 char = N;code = 78 char = T;code = 84 char = ;code = 32 char = S;code = 83 char = U;code = 85 char = P;code = 80 char = P;code = 80 char = R;code = 82 char = E;code = 69 char = S;code = 83 char = S;code = 83 char = I;code = 73 char = V;code = 86 char = E;code = 69 char = ;code = 32 char = E;code = 69 char = F;code = 70 char = F;code = 70 char = E;code = 69 char = C;code = 67 char = T;code = 84 char = S;code = 83 char = ;code = 32 char = O;code = 79 char = N;code = 78 char = ;code = 32 char = P;code = 80 char = O;code = 79 char = T;code = 84 char = A;code = 65 char = S;code = 83 char = S;code = 83 char = I;code = 73 char = U;code = 85 char = M;code = 77 char = ;code = 32 char = C;code = 67 char = U;code = 85 char = R;code = 82 char = R;code = 82 char = E;code = 69 char = N;code = 78 char = T;code = 84 char = S;code = 83 char = :;code = 58 char = ;code = 32 char = <;code = 60 char = /;code = 47 char = b;code = 98 char = >;code = 62 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = e;code = 101 char = ;code = 32 char = t;code = 116 char = r;code = 114 char = a;code = 97 char = n;code = 110 char = s;code = 115 char = i;code = 105 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = ;code = 32 char = o;code = 111 char = u;code = 117 char = t;code = 116 char = w;code = 119 char = a;code = 97 char = r;code = 114 char = d;code = 100 char = ;code = 32 char = c;code = 99 char = u;code = 117 char = r;code = 114 char = r;code = 114 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = ,;code = 44 char = ;code = 32 char = I;code = 73 char = (;code = 40 char = t;code = 116 char = o;code = 111 char = );code = 41 char = ;code = 32 char = (;code = 40 char = E;code = 69 char = C;code = 67 char = (;code = 40 char = 5;code = 53 char = 0;code = 48 char = );code = 41 char = :;code = 58 char = ;code = 32 char = 6;code = 54 char = 0;code = 48 char = .;code = 46 char = 6;code = 54 char = +;code = 43 char = /;code = 47 char = -;code = 45 char = 1;code = 49 char = 1;code = 49 char = .;code = 46 char = 4;code = 52 char = ;code = 32 char = m;code = 109 char = i;code = 105 char = c;code = 99 char = r;code = 114 char = o;code = 111 char = M;code = 77 char = ,;code = 44 char = ;code = 32 char = H;code = 72 char = i;code = 105 char = l;code = 108 char = l;code = 108 char = ;code = 32 char = c;code = 99 char = o;code = 111 char = e;code = 101 char = f;code = 102 char = f;code = 102 char = .;code = 46 char = :;code = 58 char = ;code = 32 char = 1;code = 49 char = .;code = 46 char = 0;code = 48 char = 3;code = 51 char = +;code = 43 char = /;code = 47 char = -;code = 45 char = 0;code = 48 char = .;code = 46 char = 1;code = 49 char = 1;code = 49 char = );code = 41 char = ,;code = 44 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = e;code = 101 char = ;code = 32 char = r;code = 114 char = a;code = 97 char = p;code = 112 char = i;code = 105 char = d;code = 100 char = ;code = 32 char = c;code = 99 char = o;code = 111 char = m;code = 109 char = p;code = 112 char = o;code = 111 char = n;code = 110 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = ;code = 32 char = o;code = 111 char = f;code = 102 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = e;code = 101 char = ;code = 32 char = d;code = 100 char = e;code = 101 char = l;code = 108 char = a;code = 97 char = y;code = 121 char = e;code = 101 char = d;code = 100 char = ;code = 32 char = r;code = 114 char = e;code = 101 char = c;code = 99 char = t;code = 116 char = i;code = 105 char = f;code = 102 char = i;code = 105 char = e;code = 101 char = r;code = 114 char = ,;code = 44 char = ;code = 32 char = I;code = 73 char = (;code = 40 char = K;code = 75 char = r;code = 114 char = );code = 41 char = ;code = 32 char = (;code = 40 char = E;code = 69 char = C;code = 67 char = (;code = 40 char = 5;code = 53 char = 0;code = 48 char = );code = 41 char = :;code = 58 char = ;code = 32 char = 6;code = 54 char = 3;code = 51 char = .;code = 46 char = 4;code = 52 char = +;code = 43 char = /;code = 47 char = -;code = 45 char = 6;code = 54 char = .;code = 46 char = 1;code = 49 char = ;code = 32 char = m;code = 109 char = i;code = 105 char = c;code = 99 char = r;code = 114 char = o;code = 111 char = M;code = 77 char = ,;code = 44 char = ;code = 32 char = H;code = 72 char = i;code = 105 char = l;code = 108 char = l;code = 108 char = ;code = 32 char = c;code = 99 char = o;code = 111 char = e;code = 101 char = f;code = 102 char = f;code = 102 char = .;code = 46 char = :;code = 58 char = ;code = 32 char = 1;code = 49 char = .;code = 46 char = 2;code = 50 char = 9;code = 57 char = +;code = 43 char = /;code = 47 char = -;code = 45 char = 0;code = 48 char = .;code = 46 char = 1;code = 49 char = 5;code = 53 char = );code = 41 char = ,;code = 44 char = ;code = 32 char = a;code = 97 char = n;code = 110 char = d;code = 100 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = e;code = 101 char = ;code = 32 char = s;code = 115 char = l;code = 108 char = o;code = 111 char = w;code = 119 char = ;code = 32 char = c;code = 99 char = o;code = 111 char = m;code = 109 char = p;code = 112 char = o;code = 111 char = n;code = 110 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = ;code = 32 char = o;code = 111 char = f;code = 102 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = e;code = 101 char = ;code = 32 char = d;code = 100 char = e;code = 101 char = l;code = 108 char = a;code = 97 char = y;code = 121 char = e;code = 101 char = d;code = 100 char = ;code = 32 char = r;code = 114 char = e;code = 101 char = c;code = 99 char = t;code = 116 char = i;code = 105 char = f;code = 102 char = i;code = 105 char = e;code = 101 char = r;code = 114 char = ,;code = 44 char = ;code = 32 char = I;code = 73 char = (;code = 40 char = K;code = 75 char = s;code = 115 char = );code = 41 char = ;code = 32 char = (;code = 40 char = E;code = 69 char = C;code = 67 char = (;code = 40 char = 5;code = 53 char = 0;code = 48 char = );code = 41 char = :;code = 58 char = ;code = 32 char = 2;code = 50 char = 0;code = 48 char = 2;code = 50 char = +;code = 43 char = /;code = 47 char = -;code = 45 char = 1;code = 49 char = 1;code = 49 char = ;code = 32 char = m;code = 109 char = i;code = 105 char = c;code = 99 char = r;code = 114 char = o;code = 111 char = M;code = 77 char = ,;code = 44 char = ;code = 32 char = H;code = 72 char = i;code = 105 char = l;code = 108 char = l;code = 108 char = ;code = 32 char = c;code = 99 char = o;code = 111 char = e;code = 101 char = f;code = 102 char = f;code = 102 char = .;code = 46 char = :;code = 58 char = ;code = 32 char = 0;code = 48 char = .;code = 46 char = 7;code = 55 char = 2;code = 50 char = +;code = 43 char = /;code = 47 char = -;code = 45 char = 0;code = 48 char = .;code = 46 char = 1;code = 49 char = 4;code = 52 char = );code = 41 char = ,;code = 44 char = ;code = 32 char = h;code = 104 char = o;code = 111 char = w;code = 119 char = e;code = 101 char = v;code = 118 char = e;code = 101 char = r;code = 114 char = ,;code = 44 char = ;code = 32 char = K;code = 75 char = ;code = 32 char = c;code = 99 char = h;code = 104 char = a;code = 97 char = n;code = 110 char = n;code = 110 char = e;code = 101 char = l;code = 108 char = ;code = 32 char = k;code = 107 char = i;code = 105 char = n;code = 110 char = e;code = 101 char = t;code = 116 char = i;code = 105 char = c;code = 99 char = s;code = 115 char = ;code = 32 char = w;code = 119 char = e;code = 101 char = r;code = 114 char = e;code = 101 char = ;code = 32 char = n;code = 110 char = o;code = 111 char = t;code = 116 char = ;code = 32 char = m;code = 109 char = u;code = 117 char = c;code = 99 char = h;code = 104 char = ;code = 32 char = a;code = 97 char = l;code = 108 char = t;code = 116 char = e;code = 101 char = r;code = 114 char = e;code = 101 char = d;code = 100 char = ;code = 32 char = b;code = 98 char = y;code = 121 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = y;code = 121 char = m;code = 109 char = o;code = 111 char = l;code = 108 char = .;code = 46 char = ;code = 32 char = T;code = 84 char = h;code = 104 char = e;code = 101 char = s;code = 115 char = e;code = 101 char = ;code = 32 char = e;code = 101 char = f;code = 102 char = f;code = 102 char = e;code = 101 char = c;code = 99 char = t;code = 116 char = s;code = 115 char = ;code = 32 char = o;code = 111 char = n;code = 110 char = ;code = 32 char = C;code = 67 char = a;code = 97 char = ;code = 32 char = a;code = 97 char = n;code = 110 char = d;code = 100 char = ;code = 32 char = K;code = 75 char = ;code = 32 char = c;code = 99 char = u;code = 117 char = r;code = 114 char = r;code = 114 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = s;code = 115 char = ;code = 32 char = d;code = 100 char = e;code = 101 char = v;code = 118 char = e;code = 101 char = l;code = 108 char = o;code = 111 char = p;code = 112 char = e;code = 101 char = d;code = 100 char = ;code = 32 char = r;code = 114 char = a;code = 97 char = p;code = 112 char = i;code = 105 char = d;code = 100 char = l;code = 108 char = y;code = 121 char = ;code = 32 char = (;code = 40 char = w;code = 119 char = i;code = 105 char = t;code = 116 char = h;code = 104 char = i;code = 105 char = n;code = 110 char = ;code = 32 char = 0;code = 48 char = .;code = 46 char = 5;code = 53 char = ;code = 32 char = m;code = 109 char = i;code = 105 char = n;code = 110 char = );code = 41 char = ;code = 32 char = a;code = 97 char = n;code = 110 char = d;code = 100 char = ;code = 32 char = w;code = 119 char = e;code = 101 char = r;code = 114 char = e;code = 101 char = ;code = 32 char = r;code = 114 char = e;code = 101 char = a;code = 97 char = d;code = 100 char = i;code = 105 char = l;code = 108 char = y;code = 121 char = ;code = 32 char = r;code = 114 char = e;code = 101 char = v;code = 118 char = e;code = 101 char = r;code = 114 char = s;code = 115 char = i;code = 105 char = b;code = 98 char = l;code = 108 char = e;code = 101 char = .;code = 46 char = ;code = 32 char = 5;code = 53 char = .;code = 46 char = ;code = 32 char = I;code = 73 char = n;code = 110 char = ;code = 32 char = c;code = 99 char = o;code = 111 char = n;code = 110 char = c;code = 99 char = l;code = 108 char = u;code = 117 char = s;code = 115 char = i;code = 105 char = o;code = 111 char = n;code = 110 char = ,;code = 44 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = y;code = 121 char = m;code = 109 char = o;code = 111 char = l;code = 108 char = ;code = 32 char = s;code = 115 char = u;code = 117 char = p;code = 112 char = p;code = 112 char = r;code = 114 char = e;code = 101 char = s;code = 115 char = s;code = 115 char = e;code = 101 char = d;code = 100 char = ;code = 32 char = c;code = 99 char = a;code = 97 char = r;code = 114 char = d;code = 100 char = i;code = 105 char = a;code = 97 char = c;code = 99 char = ;code = 32 char = i;code = 105 char = o;code = 111 char = n;code = 110 char = i;code = 105 char = c;code = 99 char = ;code = 32 char = c;code = 99 char = h;code = 104 char = a;code = 97 char = n;code = 110 char = n;code = 110 char = e;code = 101 char = l;code = 108 char = s;code = 115 char = ;code = 32 char = i;code = 105 char = n;code = 110 char = ;code = 32 char = a;code = 97 char = ;code = 32 char = c;code = 99 char = o;code = 111 char = n;code = 110 char = c;code = 99 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = r;code = 114 char = a;code = 97 char = t;code = 116 char = i;code = 105 char = o;code = 111 char = n;code = 110 char = -;code = 45 char = d;code = 100 char = e;code = 101 char = p;code = 112 char = e;code = 101 char = n;code = 110 char = d;code = 100 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = ;code = 32 char = m;code = 109 char = a;code = 97 char = n;code = 110 char = n;code = 110 char = e;code = 101 char = r;code = 114 char = ,;code = 44 char = ;code = 32 char = h;code = 104 char = o;code = 111 char = w;code = 119 char = e;code = 101 char = v;code = 118 char = e;code = 101 char = r;code = 114 char = ,;code = 44 char = ;code = 32 char = b;code = 98 char = o;code = 111 char = t;code = 116 char = h;code = 104 char = ;code = 32 char = d;code = 100 char = r;code = 114 char = u;code = 117 char = g;code = 103 char = -;code = 45 char = s;code = 115 char = e;code = 101 char = n;code = 110 char = s;code = 115 char = i;code = 105 char = t;code = 116 char = i;code = 105 char = v;code = 118 char = i;code = 105 char = t;code = 116 char = i;code = 105 char = e;code = 101 char = s;code = 115 char = ;code = 32 char = a;code = 97 char = s;code = 115 char = ;code = 32 char = w;code = 119 char = e;code = 101 char = l;code = 108 char = l;code = 108 char = ;code = 32 char = a;code = 97 char = s;code = 115 char = ;code = 32 char = t;code = 116 char = h;code = 104 char = e;code = 101 char = ;code = 32 char = m;code = 109 char = e;code = 101 char = c;code = 99 char = h;code = 104 char = a;code = 97 char = n;code = 110 char = i;code = 105 char = s;code = 115 char = m;code = 109 char = ;code = 32 char = o;code = 111 char = f;code = 102 char = ;code = 32 char = a;code = 97 char = c;code = 99 char = t;code = 116 char = i;code = 105 char = o;code = 111 char = n;code = 110 char = ;code = 32 char = s;code = 115 char = e;code = 101 char = e;code = 101 char = m;code = 109 char = s;code = 115 char = ;code = 32 char = t;code = 116 char = o;code = 111 char = ;code = 32 char = b;code = 98 char = e;code = 101 char = ;code = 32 char = d;code = 100 char = i;code = 105 char = f;code = 102 char = f;code = 102 char = e;code = 101 char = r;code = 114 char = e;code = 101 char = n;code = 110 char = t;code = 116 char = ;code = 32 char = w;code = 119 char = h;code = 104 char = e;code = 101 char = n;code = 110 char = ;code = 32 char = b;code = 98 char = l;code = 108 char = o;code = 111 char = c;code = 99 char = k;code = 107 char = i;code = 105 char = n;code = 110 char = g;code = 103 char = ;code = 32 char = c;code = 99 char = a;code = 97 char = l;code = 108 char = c;code = 99 char = i;code = 105 char = u;code = 117 char = m;code = 109 char = ;code = 32 char = a;code = 97 char = n;code = 110 char = d;code = 100 char = ;code = 32 char = p;code = 112 char = o;code = 111 char = t;code = 116 char = a;code = 97 char = s;code = 115 char = s;code = 115 char = i;code = 105 char = u;code = 117 char = m;code = 109 char = ;code = 32 char = c;code = 99 char = h;code = 104 char = a;code = 97 char = n;code = 110 char = n;code = 110 char = e;code = 101 char = l;code = 108 char = s;code = 115 char = .;code = 46 char = <;code = 60 char = b;code = 98 char = r;code = 114 char = /;code = 47 char = >;code = 62 result sql = 1. Concentration-dependent effects of thymol (1 - 1000 microM) was studied on action potential configuration and ionic currents in isolated canine ventricular cardiomyocytes using conventional microelectrode and patch clamp techniques. 2. Low concentration of thymol (10 microM) removed the notch of the action potential, whereas high concentrations (100 microM or higher) caused an additional shortening of action potential duration accompanied by progressive depression of plateau and reduction of V(max). 3. In the canine cells L-type Ca current (I(Ca)) was decreased by thymol in a concentration-dependent manner (EC(50): 158+/-7 microM, Hill coeff.: 2.96+/-0.43). In addition, thymol (50 - 250 microM) accelerated the inactivation of I(Ca), increased the time constant of recovery from inactivation, shifted the steady-state inactivation curve of I(Ca) leftwards, but voltage dependence of activation remained unaltered. Qualitatively similar results were obtained with thymol in ventricular myocytes isolated from healthy human hearts. 4. THYMOL DISPLAYED CONCENTRATION-DEPENDENT SUPPRESSIVE EFFECTS ON POTASSIUM CURRENTS: the transient outward current, I(to) (EC(50): 60.6+/-11.4 microM, Hill coeff.: 1.03+/-0.11), the rapid component of the delayed rectifier, I(Kr) (EC(50): 63.4+/-6.1 microM, Hill coeff.: 1.29+/-0.15), and the slow component of the delayed rectifier, I(Ks) (EC(50): 202+/-11 microM, Hill coeff.: 0.72+/-0.14), however, K channel kinetics were not much altered by thymol. These effects on Ca and K currents developed rapidly (within 0.5 min) and were readily reversible. 5. In conclusion, thymol suppressed cardiac ionic channels in a concentration-dependent manner, however, both drug-sensitivities as well as the mechanism of action seems to be different when blocking calcium and potassium channels.
Publication: Br. J. Pharmacol. 2002 May ;136(2)::330-8.
Publication Date: 2002 May
Study Author(s): Magyar, János;Szentandrássy, Norbert;Bányász, Tamás;Fülöp, László;Varró, András;Nánási, Péter P;
Institution: Department of Physiology, University Medical School of Debrecen, H-4012 Debrecen, P.O. Box 22, Hungary.
Shortcut link to this study:
1. Concentration-dependent effects of thymol (1 - 1000 microM) was studied on action potential configuration and ionic currents in isolated canine ventricular cardiomyocytes using conventional microelectrode and patch clamp techniques. 2. Low concentration of thymol (10 microM) removed the notch of the action potential, whereas high concentrations (100 microM or higher) caused an additional shortening of action potential duration accompanied by progressive depression of plateau and reduction of V(max). 3. In the canine cells L-type Ca current (I(Ca)) was decreased by thymol in a concentration-dependent manner (EC(50): 158+/-7 microM, Hill coeff.: 2.96+/-0.43). In addition, thymol (50 - 250 microM) accelerated the inactivation of I(Ca), increased the time constant of recovery from inactivation, shifted the steady-state inactivation curve of I(Ca) leftwards, but voltage dependence of activation remained unaltered. Qualitatively similar results were obtained with thymol in ventricular myocytes isolated from healthy human hearts. 4. THYMOL DISPLAYED CONCENTRATION-DEPENDENT SUPPRESSIVE EFFECTS ON POTASSIUM CURRENTS: the transient outward current, I(to) (EC(50): 60.6+/-11.4 microM, Hill coeff.: 1.03+/-0.11), the rapid component of the delayed rectifier, I(Kr) (EC(50): 63.4+/-6.1 microM, Hill coeff.: 1.29+/-0.15), and the slow component of the delayed rectifier, I(Ks) (EC(50): 202+/-11 microM, Hill coeff.: 0.72+/-0.14), however, K channel kinetics were not much altered by thymol. These effects on Ca and K currents developed rapidly (within 0.5 min) and were readily reversible. 5. In conclusion, thymol suppressed cardiac ionic channels in a concentration-dependent manner, however, both drug-sensitivities as well as the mechanism of action seems to be different when blocking calcium and potassium channels.
PMID: 12010783