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The opera opens with a brilliant festival in the gardens of the Barberigo Palace, which is attended by Genarro, Orsini, and others, all of them cordial haters of the detestable Borgias. As they leave, Lucrezia approaches, masked, in a gondola, and is received by Gubetta, with whom she has come to Venice on some secret errand. He begs her to reveal her name, but she refuses.

Five coffins are shown them, when Genarro suddenly reveals himself to Lucrezia and asks for the sixth. The horror-stricken woman again perceives that her son has been poisoned by her own hand. As his companions leave the apartment she implores Genarro to take the antidote once more, and at last reveals herself as his mother.

When Lucrezia discovers the insult, she demands of the Duke that the guilty person shall be arrested and condemned to death. The Duke has already seized Genarro, and agrees to carry out his wife's demands. When the prisoner is brought before them for judgment, she is horror-stricken to find he is her son.

The last act opens at a banquet in the palace of the Princess Negroni, which is attended by Genarro and his friends, Lucrezia, meanwhile, supposing that he has gone to Venice. During the repast she has managed to poison their wine. In the midst of the gay revel Orsini sings the popular drinking-song, "Il segreto per esser felici," which is now familiar the world over.

The second act opens in the public square of Ferrara, with the palace of the Borgias on the right. In the next scene Genarro, who has been taunted by his friends with being a victim of Lucrezia's fascinations, recklessly rushes up to the palace door and strikes off the first letter of her name with his dagger.

It is necessary to the comprehension of the story of the opera, however, to state that she had an illegitimate son, named Genarro, who was left when an infant with a fisherman, but who subsequently entered the Venetian army and rose to an eminent rank.