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In 1444, Lucrezia married Piero di Cosimo de' Medici, the de facto leader of Florence. Five years later, she gave birth to a son named Lorenzo. Lorenzo was considered the brightest of their children, and raised mainly by Lucrezia due to Piero's poor health.
As a poet, she introduced Lorenzo to prominent artists of the day, instilling in him a love of art and culture. Around 1455, he fell into the Arno river, only to be rescued by the Assassin Giovanni Auditore da Firenze. When Lorenzo regained consciousness, a tearful Lucrezia told him what had happened, and a relationship soon began between the House of Medici and the House of Auditore.