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According to Mainwaring, in 1706 Handel traveled to Italy at the invitation of Ferdinando de' Medici, but Mainwaring must have been confused. It was Gian Gastone de' Medici, whom Handel had met in 1703/1704 in Hamburg. Ferdinando had made Florence Italy's musical capital, attracting the leading talents of his day. He had a keen interest in opera. In Italy Handel met librettist Antonio Salvi, with whom he later collaborated. He had a rumored love affair with Vittoria Tarquini, a singer. Handel left for Rome and, since opera was (temporarily) banned in the Papal States, composed sacred music for the Roman clergy. His famous Dixit Dominus (1707) is from this era. He also composed cantatas in pastoral style for musical gatherings in the Palace of Cardinals Pietro Ottoboni, Benedetto Pamphili and Carlo Colonna. Two oratorios, La Resurrezione and Il Trionfo del Tempo, were produced in a private setting for Ruspoli and Ottoboni in 1709 and 1710, respectively. Rodrigo, his first all-Italian opera, was produced in the Cocomero theatre in Florence in 1707. Agrippina was first produced in 1709 at Teatro San Giovanni Grisostomo, the prettiest theatre at Venice, owned by the Grimanis. The opera, with a libretto by cardinal Vincenzo Grimani, ran for an unprecedented 27 performances. It showed remarkable maturity and established Handel's reputation as a composer of opera. The audience, thunderstruck with the grandeur and sublimity of his style, applauded for Il caro Sassone.

Italy was a great center of musical activity particularly during the first 20 years of the 1700s, and Handel was to meet and exchange ideas with many of the leading composers, musicians and nobility of the time - and not only Italians, for it was obligatory for every cultural and music-loving person of any rank or nobility to do the Grand European Tour which naturally included the main Italian cultural centers. Thus on his travels around Italy Handel also made a number of useful contacts including the Duke of Manchester, the English Ambassador, and most significantly Prince Ernst August of Hanover, brother of the Elector (later King George I of England) who pressed him to visit Hanover. The Prince may also have intimated the possibility of a post at the Hanoverian court, for when Handel left Italy early in 1710 it was for Hanover, where he was in fact appointed Capellmeister to the Elector, George Louis, who immediately packed him off on a twelve months' leave of absence to visit England. The Royal Houses of Britain and Germany had always been closely inter-related, and the Act of Settlement of 1701 which secured the Protestant succession to the Crown of England, had made Handel's Hanoverian employer George Louis' mother heiress-presumptive to the throne of Great Britain. Thus the Elector George Louis would have been anxious to have Handel spy out the land and report back to him on the London musical, social and political scene.