Napoli striker Edinson Cavani missed a penalty to get his side back into the game.
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Napoli crushed Roma 4-1 thanks to a stunning hat-trick from Uruguay international Edinson Cavani.
Pitching for the Padres will be Edinson Volquez, set to make his third consecutive opening day start.
Palermo extended their unbeaten league run to five games with Edinson Cavani scoring the only goal against Atalanta from the penalty spot.
While Serie A strikers such as Milan's Zlatan Ibrahimovich and Napoli's Edinson Cavani are admired throughout Europe, Di Natale is elatively unknown outside of Italy.
He had an RBI single in the second off an ineffective Edinson Volquez (0-1), then drew a leadoff walk and scored in a three-run fourth.
Earlier Sunday, Edinson Cavani took his Serie A-leading goal tally to 28 as second-placed Napoli came from behind to beat Siena 2-1 thanks to Marek Hamsik's injury-time winner.
Lavezzi had a shot deflected wide off left-back before he lofted a ball to release Edinson Cavani on the home goal only for the Napoli striker to blaze horribly over.
The result left Milan 13 points behind leaders Juventus and four adrift of next weekend's opponent Napoli -- who beat lowly Genoa 2-0 later Sunday despite a second-half penalty miss by Edinson Cavani.
The Ajax keeper had another nervous moment at the start of the second half when he beat Edinson Cavani to a through ball but failed to make a proper clearance and Van Bronkhorst had to clear Alvaro Pereira's curling shot off the line.
Having navigated a tricky opening game against France relatively unscathed and knowing here lay their chance to seize control of Group A, Uruguay opted for a three man strike force, bringing in Edinson Cavani to partner Suarez, with Atletico Madrid's Forlan playing in a withdrawn attacking role.
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