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大明永乐皇帝病重，锦衣卫副指挥使李毅，奉命护送西藏大喇嘛进京，为皇帝诵经祈福。半路遇袭，遭东厂高手伏击，拼命搏杀之际，却发现，大喇嘛是个女人。而这一切，都是锦衣卫指挥使纪纲的安排。还没等李毅调查清查，之前遭纪纲陷害的解缙就离奇的自杀了，李毅背上了谋杀钦犯的大罪。 刑场之上，李毅逃过一劫，东厂赵忠和锦衣卫纪纲能取胜，大喇嘛的阴谋没有得逞。
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