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After a quiet start, Inter took the lead with their first real opening of the match. Rodrigo Palacio was sent free down the right hand side and his low cross into the box was turned home by Mauro Icardi at the front post.
Lopez stepped up to take the kick, but he saw his low effort turned behind by Handanovic.
Things were to get even worse for the Blucerchiati just moments later, as Eder was dismissed for picking up two yellow cards in quick succession.
Despite their man disadvantage, Sampdoria continued to threaten and Lopez worked some space on the edge of the box before firing in a strike that was tipped wide by the keeper.
They came close again moments later when Gianluca Sansone's free kick looked to be heading into the top corner, but Handanovic clawed his effort over the bar.
With a minute of the first half remaining, Handanovic denied Sampdoria again as he stretched out a hand to push Roberto Soriano's effort wide.
After the break Palacio came close to extending Inter's lead, but lashed his strike from the edge of the box wide of the post.
The Argentina had another chance to score when he was slipped into the box, but saw his fierce effort from a tight angle beaten away by Angelo da Costa Junior.
Three minutes later the Nerazzurri further extended their advantage, as Icardi was found in space inside the box by Palacio, before slotting an effort past Costa.
Inter continued to dominate and Palacio added a fourth goal in the 79th minute when he was slipped into the box by Ricky Alvarez and placed a composed strike into the bottom corner to wrap up the three points.