|
|
char = P;code = 80
char = h;code = 104
char = y;code = 121
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = b;code = 98
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = o;code = 111
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 = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = o;code = 111
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 = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = c;code = 99
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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = k;code = 107
char = e;code = 101
char = n;code = 110
char = y;code = 121
char = l;code = 108
char = b;code = 98
char = e;code = 101
char = n;code = 110
char = z;code = 122
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = .;code = 46
result sql = Physiologically based biokinetic model of bioactivation and detoxification of the alkenylbenzene methyleugenol in rat.
Physiologically based biokinetic model of bioactivation and detoxification of the alkenylbenzene methyleugenol in rat.char = T;code = 84
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = u;code = 117
char = d;code = 100
char = y;code = 121
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = f;code = 102
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = y;code = 121
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
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char = b;code = 98
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = o;code = 111
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 = ;code = 32
char = (;code = 40
char = P;code = 80
char = B;code = 66
char = B;code = 66
char = K;code = 75
char = );code = 41
char = ;code = 32
char = m;code = 109
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char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = a;code = 97
char = l;code = 108
char = k;code = 107
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char = b;code = 98
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char = z;code = 122
char = e;code = 101
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char = e;code = 101
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char = m;code = 109
char = e;code = 101
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char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
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char = o;code = 111
char = l;code = 108
char = ;code = 32
char = i;code = 105
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char = ;code = 32
char = b;code = 98
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char = e;code = 101
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char = i;code = 105
char = n;code = 110
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char = v;code = 118
char = i;code = 105
char = t;code = 116
char = r;code = 114
char = o;code = 111
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = a;code = 97
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = u;code = 117
char = s;code = 115
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char = g;code = 103
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char = e;code = 101
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char = a;code = 97
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char = t;code = 116
char = i;code = 105
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char = s;code = 115
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char = f;code = 102
char = r;code = 114
char = a;code = 97
char = c;code = 99
char = t;code = 116
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char = o;code = 111
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char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = i;code = 105
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char = ;code = 32
char = s;code = 115
char = i;code = 105
char = l;code = 108
char = i;code = 105
char = c;code = 99
char = o;code = 111
char = ;code = 32
char = d;code = 100
char = e;code = 101
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char = i;code = 105
char = v;code = 118
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = c;code = 99
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char = e;code = 101
char = f;code = 102
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = i;code = 105
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char = n;code = 110
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char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = o;code = 111
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char = ;code = 32
char = p;code = 112
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char = a;code = 97
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char = e;code = 101
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char = s;code = 115
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = v;code = 118
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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = l;code = 108
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char = t;code = 116
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = u;code = 117
char = r;code = 114
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char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
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char = m;code = 109
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char = w;code = 119
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char = s;code = 115
char = ;code = 32
char = b;code = 98
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char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = o;code = 111
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char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = v;code = 118
char = i;code = 105
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = l;code = 108
char = y;code = 121
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 = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
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char = e;code = 101
char = d;code = 100
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char = a;code = 97
char = l;code = 108
char = k;code = 107
char = e;code = 101
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char = l;code = 108
char = b;code = 98
char = e;code = 101
char = n;code = 110
char = z;code = 122
char = e;code = 101
char = n;code = 110
char = e;code = 101
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char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = g;code = 103
char = o;code = 111
char = l;code = 108
char = e;code = 101
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char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = e;code = 101
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = t;code = 116
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char = c;code = 99
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char = m;code = 109
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char = i;code = 105
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char = ;code = 32
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char = k;code = 107
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char = a;code = 97
char = s;code = 115
char = ;code = 32
char = m;code = 109
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char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
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char = f;code = 102
char = a;code = 97
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char = ,;code = 44
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char = a;code = 97
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char = e;code = 101
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char = b;code = 98
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char = s;code = 115
char = u;code = 117
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char = E;code = 69
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char = P;code = 80
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char = B;code = 66
char = K;code = 75
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char = e;code = 101
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char = P;code = 80
char = B;code = 66
char = B;code = 66
char = K;code = 75
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char = r;code = 114
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char = e;code = 101
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char = t;code = 116
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char = ;code = 32
char = f;code = 102
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char = r;code = 114
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char = i;code = 105
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char = 5;code = 53
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char = a;code = 97
char = l;code = 108
char = l;code = 108
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char = l;code = 108
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char = l;code = 108
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char = 1;code = 49
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char = r;code = 114
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char = h;code = 104
char = y;code = 121
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char = u;code = 117
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char = e;code = 101
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char = o;code = 111
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char = g;code = 103
char = l;code = 108
char = u;code = 117
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char = u;code = 117
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char = n;code = 110
char = i;code = 105
char = d;code = 100
char = e;code = 101
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char = t;code = 116
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char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = c;code = 99
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char = s;code = 115
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char = d;code = 100
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char = n;code = 110
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char = e;code = 101
char = n;code = 110
char = t;code = 116
char = a;code = 97
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char = e;code = 101
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
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char = t;code = 116
char = a;code = 97
char = b;code = 98
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char = i;code = 105
char = t;code = 116
char = e;code = 101
char = s;code = 115
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char = e;code = 101
char = x;code = 120
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char = e;code = 101
char = d;code = 100
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char = ;code = 32
char = u;code = 117
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char = r;code = 114
char = e;code = 101
char = p;code = 112
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char = l;code = 108
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char = a;code = 97
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char = ,;code = 44
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char = i;code = 105
char = c;code = 99
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char = A;code = 65
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = 1;code = 49
char = ';code = 39
char = -;code = 45
char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = g;code = 103
char = l;code = 108
char = u;code = 117
char = c;code = 99
char = u;code = 117
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = d;code = 100
char = e;code = 101
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char = ;code = 32
char = 1;code = 49
char = ';code = 39
char = -;code = 45
char = o;code = 111
char = x;code = 120
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = 1;code = 49
char = ';code = 39
char = -;code = 45
char = s;code = 115
char = u;code = 117
char = l;code = 108
char = f;code = 102
char = o;code = 111
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
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 = 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 = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = m;code = 109
char = p;code = 112
char = o;code = 111
char = r;code = 114
char = t;code = 116
char = a;code = 97
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 = 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 = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = w;code = 119
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = v;code = 118
char = a;code = 97
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
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 = w;code = 119
char = a;code = 97
char = y;code = 121
char = ,;code = 44
char = ;code = 32
char = l;code = 108
char = e;code = 101
char = a;code = 97
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
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 = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = o;code = 111
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
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 = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = h;code = 104
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
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char = r;code = 114
char = /;code = 47
char = >;code = 62
result sql = The present study defines a physiologically based biokinetic (PBBK) model for the alkenylbenzene methyleugenol in rat based on in vitro metabolic parameters determined using relevant tissue fractions, in silico derived partition coefficients, and physiological parameters derived from the literature. The model was based on the model previously developed for the related alkenylbenzene estragole and consists of eight compartments including liver, lung, and kidney as metabolizing compartments, and separate compartments for fat, arterial blood, venous blood, richly perfused and slowly perfused tissues. Evaluation of the model was performed by comparing the PBBK predicted concentration of methyleugenol in the venous compartment to methyleugenol plasma levels reported in the literature, by comparing the PBBK predicted dose-dependent percentage of formation of 2-hydroxy-4,5-dimethoxyallylbenzene, 3-hydroxy-4-methoxyallylbenzene, and 1'-hydroxymethyleugenol glucuronide to the corresponding percentage of metabolites excreted in urine reported in the literature, which were demonstrated to be in the same order of magnitude. With the model obtained the relative extent of bioactivation and detoxification of methyleugenol at different oral doses was examined. At low doses, formation of 3-(3,4-dimethoxyphenyl)-2-propen-1-ol and methyleugenol-2',3'-oxide leading to detoxification appear to be the major metabolic pathways, occurring in the liver. At high doses, the model reveals a relative increase in the formation of the proximate carcinogenic metabolite 1'-hydroxymethyleugenol, occurring in the liver. This relative increase in formation of 1'-hydroxymethyleugenol leads to a relative increase in formation of 1'-hydroxymethyleugenol glucuronide, 1'-oxomethyleugenol, and 1'-sulfooxymethyleugenol the latter being the ultimate carcinogenic metabolite of methyleugenol. These results indicate that the relative importance of different metabolic pathways of methyleugenol may vary in a dose-dependent way, leading to a relative increase in bioactiviation of methyleugenol at higher doses.
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char = y;code = 121
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = b;code = 98
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = o;code = 111
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 = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = o;code = 111
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 = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = c;code = 99
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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = l;code = 108
char = k;code = 107
char = e;code = 101
char = n;code = 110
char = y;code = 121
char = l;code = 108
char = b;code = 98
char = e;code = 101
char = n;code = 110
char = z;code = 122
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = .;code = 46
result sql = Physiologically based biokinetic model of bioactivation and detoxification of the alkenylbenzene methyleugenol in rat.
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char = e;code = 101
char = ;code = 32
char = p;code = 112
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char = n;code = 110
char = t;code = 116
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = u;code = 117
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char = y;code = 121
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = f;code = 102
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = s;code = 115
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char = a;code = 97
char = ;code = 32
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char = h;code = 104
char = y;code = 121
char = s;code = 115
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char = o;code = 111
char = g;code = 103
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
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char = b;code = 98
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = o;code = 111
char = k;code = 107
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char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
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char = B;code = 66
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char = k;code = 107
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char = m;code = 109
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char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
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char = o;code = 111
char = l;code = 108
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = b;code = 98
char = a;code = 97
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char = i;code = 105
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char = a;code = 97
char = b;code = 98
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char = a;code = 97
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char = e;code = 101
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char = i;code = 105
char = n;code = 110
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = r;code = 114
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char = l;code = 108
char = i;code = 105
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char = p;code = 112
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char = i;code = 105
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = c;code = 99
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char = e;code = 101
char = f;code = 102
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = i;code = 105
char = e;code = 101
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char = t;code = 116
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
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char = h;code = 104
char = y;code = 121
char = s;code = 115
char = i;code = 105
char = o;code = 111
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char = o;code = 111
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char = c;code = 99
char = a;code = 97
char = l;code = 108
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char = ;code = 32
char = d;code = 100
char = e;code = 101
char = r;code = 114
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char = v;code = 118
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
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char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = l;code = 108
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = u;code = 117
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char = e;code = 101
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char = e;code = 101
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char = o;code = 111
char = u;code = 117
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char = y;code = 121
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char = d;code = 100
char = e;code = 101
char = v;code = 118
char = e;code = 101
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char = o;code = 111
char = p;code = 112
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = f;code = 102
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char = t;code = 116
char = h;code = 104
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char = r;code = 114
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char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
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char = k;code = 107
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char = l;code = 108
char = b;code = 98
char = e;code = 101
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char = z;code = 122
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = g;code = 103
char = o;code = 111
char = l;code = 108
char = e;code = 101
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char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = e;code = 101
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = t;code = 116
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
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char = i;code = 105
char = n;code = 110
char = c;code = 99
char = l;code = 108
char = u;code = 117
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = ,;code = 44
char = ;code = 32
char = l;code = 108
char = u;code = 117
char = n;code = 110
char = g;code = 103
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = k;code = 107
char = i;code = 105
char = d;code = 100
char = n;code = 110
char = e;code = 101
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = z;code = 122
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = c;code = 99
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char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = e;code = 101
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = f;code = 102
char = a;code = 97
char = t;code = 116
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = o;code = 111
char = o;code = 111
char = d;code = 100
char = ,;code = 44
char = ;code = 32
char = v;code = 118
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = l;code = 108
char = o;code = 111
char = o;code = 111
char = d;code = 100
char = ,;code = 44
char = ;code = 32
char = r;code = 114
char = i;code = 105
char = c;code = 99
char = h;code = 104
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = f;code = 102
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = l;code = 108
char = o;code = 111
char = w;code = 119
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = f;code = 102
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = i;code = 105
char = s;code = 115
char = s;code = 115
char = u;code = 117
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = E;code = 69
char = v;code = 118
char = a;code = 97
char = l;code = 108
char = u;code = 117
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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = P;code = 80
char = B;code = 66
char = B;code = 66
char = K;code = 75
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = t;code = 116
char = e;code = 101
char = d;code = 100
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 = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = v;code = 118
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = o;code = 111
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char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
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char = o;code = 111
char = l;code = 108
char = ;code = 32
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = m;code = 109
char = a;code = 97
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char = l;code = 108
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = s;code = 115
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = p;code = 112
char = o;code = 111
char = r;code = 114
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char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = l;code = 108
char = i;code = 105
char = t;code = 116
char = e;code = 101
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char = a;code = 97
char = t;code = 116
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = b;code = 98
char = y;code = 121
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char = c;code = 99
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char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = P;code = 80
char = B;code = 66
char = B;code = 66
char = K;code = 75
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = c;code = 99
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char = e;code = 101
char = d;code = 100
char = ;code = 32
char = d;code = 100
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char = s;code = 115
char = e;code = 101
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char = e;code = 101
char = p;code = 112
char = e;code = 101
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char = d;code = 100
char = e;code = 101
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char = t;code = 116
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = 2;code = 50
char = -;code = 45
char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = y;code = 121
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char = 4;code = 52
char = ,;code = 44
char = 5;code = 53
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char = i;code = 105
char = m;code = 109
char = e;code = 101
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char = h;code = 104
char = o;code = 111
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char = y;code = 121
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = l;code = 108
char = b;code = 98
char = e;code = 101
char = n;code = 110
char = z;code = 122
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = 3;code = 51
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char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = y;code = 121
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char = 4;code = 52
char = -;code = 45
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = o;code = 111
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char = y;code = 121
char = a;code = 97
char = l;code = 108
char = l;code = 108
char = y;code = 121
char = l;code = 108
char = b;code = 98
char = e;code = 101
char = n;code = 110
char = z;code = 122
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = 1;code = 49
char = ';code = 39
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char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
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char = o;code = 111
char = l;code = 108
char = ;code = 32
char = g;code = 103
char = l;code = 108
char = u;code = 117
char = c;code = 99
char = u;code = 117
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = r;code = 114
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = p;code = 112
char = o;code = 111
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char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = u;code = 117
char = r;code = 114
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char = e;code = 101
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char = e;code = 101
char = p;code = 112
char = o;code = 111
char = r;code = 114
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char = e;code = 101
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char = h;code = 104
char = e;code = 101
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char = i;code = 105
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char = a;code = 97
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char = u;code = 117
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char = e;code = 101
char = ,;code = 44
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char = w;code = 119
char = h;code = 104
char = i;code = 105
char = c;code = 99
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char = e;code = 101
char = r;code = 114
char = e;code = 101
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char = e;code = 101
char = m;code = 109
char = o;code = 111
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char = s;code = 115
char = t;code = 116
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char = a;code = 97
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char = e;code = 101
char = d;code = 100
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char = o;code = 111
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char = b;code = 98
char = e;code = 101
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char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = s;code = 115
char = a;code = 97
char = m;code = 109
char = e;code = 101
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char = o;code = 111
char = r;code = 114
char = d;code = 100
char = e;code = 101
char = r;code = 114
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = g;code = 103
char = n;code = 110
char = i;code = 105
char = t;code = 116
char = u;code = 117
char = d;code = 100
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = W;code = 87
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char = t;code = 116
char = h;code = 104
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
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char = o;code = 111
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char = a;code = 97
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char = e;code = 101
char = d;code = 100
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char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
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char = i;code = 105
char = v;code = 118
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char = e;code = 101
char = x;code = 120
char = t;code = 116
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char = n;code = 110
char = t;code = 116
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = b;code = 98
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char = o;code = 111
char = a;code = 97
char = c;code = 99
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char = i;code = 105
char = v;code = 118
char = a;code = 97
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char = a;code = 97
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char = d;code = 100
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char = o;code = 111
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char = f;code = 102
char = i;code = 105
char = c;code = 99
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 = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
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char = o;code = 111
char = l;code = 108
char = ;code = 32
char = a;code = 97
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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 = o;code = 111
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char = a;code = 97
char = l;code = 108
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = e;code = 101
char = x;code = 120
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = n;code = 110
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char = d;code = 100
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = t;code = 116
char = ;code = 32
char = l;code = 108
char = o;code = 111
char = w;code = 119
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
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 = 3;code = 51
char = -;code = 45
char = (;code = 40
char = 3;code = 51
char = ,;code = 44
char = 4;code = 52
char = -;code = 45
char = d;code = 100
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = p;code = 112
char = h;code = 104
char = e;code = 101
char = n;code = 110
char = y;code = 121
char = l;code = 108
char = );code = 41
char = -;code = 45
char = 2;code = 50
char = -;code = 45
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = p;code = 112
char = e;code = 101
char = n;code = 110
char = -;code = 45
char = 1;code = 49
char = -;code = 45
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = -;code = 45
char = 2;code = 50
char = ';code = 39
char = ,;code = 44
char = 3;code = 51
char = ';code = 39
char = -;code = 45
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = e;code = 101
char = a;code = 97
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = t;code = 116
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = p;code = 112
char = p;code = 112
char = e;code = 101
char = a;code = 97
char = r;code = 114
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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = j;code = 106
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = w;code = 119
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = o;code = 111
char = c;code = 99
char = c;code = 99
char = u;code = 117
char = r;code = 114
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = t;code = 116
char = ;code = 32
char = h;code = 104
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
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 = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
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 = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = i;code = 105
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = 1;code = 49
char = ';code = 39
char = -;code = 45
char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ,;code = 44
char = ;code = 32
char = o;code = 111
char = c;code = 99
char = c;code = 99
char = u;code = 117
char = r;code = 114
char = r;code = 114
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = r;code = 114
char = .;code = 46
char = ;code = 32
char = T;code = 84
char = h;code = 104
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
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 = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
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 = 1;code = 49
char = ';code = 39
char = -;code = 45
char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = l;code = 108
char = e;code = 101
char = a;code = 97
char = d;code = 100
char = s;code = 115
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
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 = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
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 = 1;code = 49
char = ';code = 39
char = -;code = 45
char = h;code = 104
char = y;code = 121
char = d;code = 100
char = r;code = 114
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = g;code = 103
char = l;code = 108
char = u;code = 117
char = c;code = 99
char = u;code = 117
char = r;code = 114
char = o;code = 111
char = n;code = 110
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = 1;code = 49
char = ';code = 39
char = -;code = 45
char = o;code = 111
char = x;code = 120
char = o;code = 111
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = 1;code = 49
char = ';code = 39
char = -;code = 45
char = s;code = 115
char = u;code = 117
char = l;code = 108
char = f;code = 102
char = o;code = 111
char = o;code = 111
char = x;code = 120
char = y;code = 121
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = u;code = 117
char = l;code = 108
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = r;code = 114
char = c;code = 99
char = i;code = 105
char = n;code = 110
char = o;code = 111
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
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 = 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 = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = m;code = 109
char = p;code = 112
char = o;code = 111
char = r;code = 114
char = t;code = 116
char = a;code = 97
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 = 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 = m;code = 109
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = o;code = 111
char = l;code = 108
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = w;code = 119
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = m;code = 109
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = v;code = 118
char = a;code = 97
char = r;code = 114
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
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 = w;code = 119
char = a;code = 97
char = y;code = 121
char = ,;code = 44
char = ;code = 32
char = l;code = 108
char = e;code = 101
char = a;code = 97
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
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 = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = i;code = 105
char = o;code = 111
char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
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 = m;code = 109
char = e;code = 101
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = l;code = 108
char = e;code = 101
char = u;code = 117
char = g;code = 103
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = h;code = 104
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
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 = The present study defines a physiologically based biokinetic (PBBK) model for the alkenylbenzene methyleugenol in rat based on in vitro metabolic parameters determined using relevant tissue fractions, in silico derived partition coefficients, and physiological parameters derived from the literature. The model was based on the model previously developed for the related alkenylbenzene estragole and consists of eight compartments including liver, lung, and kidney as metabolizing compartments, and separate compartments for fat, arterial blood, venous blood, richly perfused and slowly perfused tissues. Evaluation of the model was performed by comparing the PBBK predicted concentration of methyleugenol in the venous compartment to methyleugenol plasma levels reported in the literature, by comparing the PBBK predicted dose-dependent percentage of formation of 2-hydroxy-4,5-dimethoxyallylbenzene, 3-hydroxy-4-methoxyallylbenzene, and 1'-hydroxymethyleugenol glucuronide to the corresponding percentage of metabolites excreted in urine reported in the literature, which were demonstrated to be in the same order of magnitude. With the model obtained the relative extent of bioactivation and detoxification of methyleugenol at different oral doses was examined. At low doses, formation of 3-(3,4-dimethoxyphenyl)-2-propen-1-ol and methyleugenol-2',3'-oxide leading to detoxification appear to be the major metabolic pathways, occurring in the liver. At high doses, the model reveals a relative increase in the formation of the proximate carcinogenic metabolite 1'-hydroxymethyleugenol, occurring in the liver. This relative increase in formation of 1'-hydroxymethyleugenol leads to a relative increase in formation of 1'-hydroxymethyleugenol glucuronide, 1'-oxomethyleugenol, and 1'-sulfooxymethyleugenol the latter being the ultimate carcinogenic metabolite of methyleugenol. These results indicate that the relative importance of different metabolic pathways of methyleugenol may vary in a dose-dependent way, leading to a relative increase in bioactiviation of methyleugenol at higher doses.
Publication: Toxicol In Vitro 2011 Feb ;25(1)::267-85. :doi: 10.1016/j.tiv.2010.08.019.
Publication Date: 2011 Feb
Study Author(s): Al-Subeihi, Ala A A;Spenkelink, Bert;Rachmawati, Novalia;Boersma, Marelle G;Punt, Ans;Vervoort, Jacques;van Bladeren, Peter J;Rietjens, Ivonne M C M;
Institution: Division of Toxicology, Wageningen University, Wageningen, The Netherlands. [email protected]
Shortcut link to this study:
Publication Date: 2011 Feb
Study Author(s): Al-Subeihi, Ala A A;Spenkelink, Bert;Rachmawati, Novalia;Boersma, Marelle G;Punt, Ans;Vervoort, Jacques;van Bladeren, Peter J;Rietjens, Ivonne M C M;
Institution: Division of Toxicology, Wageningen University, Wageningen, The Netherlands. [email protected]
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The present study defines a physiologically based biokinetic (PBBK) model for the alkenylbenzene methyleugenol in rat based on in vitro metabolic parameters determined using relevant tissue fractions, in silico derived partition coefficients, and physiological parameters derived from the literature. The model was based on the model previously developed for the related alkenylbenzene estragole and consists of eight compartments including liver, lung, and kidney as metabolizing compartments, and separate compartments for fat, arterial blood, venous blood, richly perfused and slowly perfused tissues. Evaluation of the model was performed by comparing the PBBK predicted concentration of methyleugenol in the venous compartment to methyleugenol plasma levels reported in the literature, by comparing the PBBK predicted dose-dependent percentage of formation of 2-hydroxy-4,5-dimethoxyallylbenzene, 3-hydroxy-4-methoxyallylbenzene, and 1'-hydroxymethyleugenol glucuronide to the corresponding percentage of metabolites excreted in urine reported in the literature, which were demonstrated to be in the same order of magnitude. With the model obtained the relative extent of bioactivation and detoxification of methyleugenol at different oral doses was examined. At low doses, formation of 3-(3,4-dimethoxyphenyl)-2-propen-1-ol and methyleugenol-2',3'-oxide leading to detoxification appear to be the major metabolic pathways, occurring in the liver. At high doses, the model reveals a relative increase in the formation of the proximate carcinogenic metabolite 1'-hydroxymethyleugenol, occurring in the liver. This relative increase in formation of 1'-hydroxymethyleugenol leads to a relative increase in formation of 1'-hydroxymethyleugenol glucuronide, 1'-oxomethyleugenol, and 1'-sulfooxymethyleugenol the latter being the ultimate carcinogenic metabolite of methyleugenol. These results indicate that the relative importance of different metabolic pathways of methyleugenol may vary in a dose-dependent way, leading to a relative increase in bioactiviation of methyleugenol at higher doses.
PMID: 20828604
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