Hoping to rebound from their divisional home loss to the Redskins, the Eagles flew to Candlestick Park for a Week 5 Sunday night duel with the San Francisco 49ers. Kevin Kolb was back under center for the eagles in this game .Philadelphia trailed early in the first quarter as 49ers quarterback Alex Smith completed a 7-yard touchdown pass to wide receiver Michael Crabtree, yet the Eagles responded with quarterback Kevin Kolb finding tight end Brent Celek on an 8-yard touchdown pass. Philadelphia would take the lead in the second quarter as kicker David Akers booted a 33-yard field goal, followed a 39-yard touchdown run from running back LeSean McCoy. Afterwards, San Francisco would close out the half with a 50-yard field goal from kicker Joe Nedney. After a scoreless third quarter, the Eagles added onto their lead in the fourth quarter as safety Quintin Mikell returned a fumble 52 yards for a touchdown. The 49ers began to rally as Smith connected a 7-yard touchdown pass to tight end Vernon Davis, yet Akers came right back as he gave Philadelphia a 45-yard field goal. San Francisco tried to rally as Smith completed a 1-yard touchdown pass to running back Frank Gore, yet Philadelphia's defense held on to preserve the victory.

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