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The painting was commissioned by Pope Julius II in honor of his late uncle, Pope Sixtus IV, as an altarpiece for the basilica church of the Benedictine Monastery of San Sisto in Piacenza, with which the Rovere family had a long-standing relationship. The commission required that the painting depict both Saints Sixtus and Barbara. Legend has it that when Antonio da Correggio first laid eyes on the piece, he was inspired to cry, "And I also, I am a painter!"